0:08 What's up, ninja nerds? In this video today, we're going to be talking about anti-neoplastic agents. And this is going to be a monster of a lecture. The reason why is it's going to combine aspects of step one, but it's also going to really talk about more of the step two, more of the decision making, more of the therapeutics, more of the adverse effects. But I think in order for us to understand these things, we have to build up a little bit of foundation in the physiology. So we'll talk about the cell cycle briefly. We'll talk about the cell regulation and then we'll talk about some other kind of immune and angioenic kind of influences as well. Then what we'll do is we'll go into each individual kind of anti-neoplastic agent. Talk about their names, talk about how they work. And then what we'll do is we'll go into the indications. Why do I give this one? Why do I give this combination? And then lastly, we'll talk about what are some things to monitor for because of the potential for the adverse effects and toxicities of some of these kind of anti-neoplastic agents. However, this is going to be a really long lecture. If you want like a quick little summary or a little recap of all 1:05 of this kind of more step one content, you can go down in the chapters and you'll be able to go to the little summary part and you can kind of watch the whole summary which is going to explain most of the video and then we're going to start talking a lot about the indications and the adverse effects. All right, let's get started. All right, my friends. We're not going to go crazy. We talked about this more in our cell cycle video. If you guys want to watch that video, go and click on that video. It's going to be in our cell biology playlist, and we go over the cell cycle in a lot more detail. This is going to be more of just kind of a quick little reminder, if you will. So, when we talk about the cell cycle, let's say that we have a cell, right? You just replicas took a cell, you divided into two daughter cells, right? And that's going to be through a specific phase called the mitosis or the Mphase. But once you have this cell, this cell can either kind of um well it has two options. One is it can go into a resting state, right? And so we have a phase here and we call this phase the G0 phase. And this is basically the phase where I' I'd say in the most simplistic way possible, 2:01 this is the quiescent phase or the resting phase. This is where most of your cells are basically at rest. They're not kind of actively replicating and dividing. They're mature differentiated cells. That's going to be one of those phases. an interphase really we'll talk about the different components but one of those we kind of consider the GV zero phase or that quiescent area where the cells are resting they're not really constantly actively replicating they're more in their mature differentiated states another option is this cell right what it can do is it can start kind of taking and getting ready to undergo DNA replication right and so let's say that for example here I have you know a male chromosome and then we have the female chromosome right and then you also have a bunch of other things proteins and enzymes and organels. When I want to take this cell and get it ready to divide, I need to start getting a lot of enzymes that are needed for kind of the whole DNA replication process. I also need to start getting organels to be built up so I can share the organels between two cells. And so that's what usually happens going from this part to 3:01 this part. And so that's what we would see is we would see kind of the same number of chromosomes we haven't replicated at at this point, but we may have more proteins. We may have more enzymes that are needed for the DNA replication process. We may have more organels. This phase here is called the G1 phase. So it's called the G1 phase. All right. So that's the next part of interphase. So we have the G0 phase which is the quiescent one. It's the resting state. That's where most of the cells are in the rest. They're not actively different. They're not actively kind of replicating. They're mature differentiated. G1, they're getting ready to start kind of preparing for the replication process. They're making more organels. They're increasing proteins and enzymes needed for DNA replication. Then what's going to happen is we're going to take this cell and look what changes here. We go from having this part here and we duplicate we duplicate our chromosomes. When you go from this cell to this cell and you duplicate your number of chromosomes, you underwent the DNA replication process. And at this 4:03 stage is this is called the S phase. So this is where DNA replication takes place, right? A lot of this should sound familiar from your basic biology, right? Then what we're going to do is we're going to take this cell which has these kinds of extra. Now in this case, we've kind of duplicated the DNA. We need to start getting these kind of cells ready to share the DNA. So I'm going to start increasing the cell size. I'm going to start getting the cytoplasm bigger. I'm going to start making more of the enzymes that I need to help me to start separating this cell. And that's when we get ready to go into this next stage. And this is called the G2 phase. This is called the G2 phase, right? The G2 phase. And all that's happening here is you're kind of just getting things ready. You're kind of getting the cell ready. You you're increasing the number of proteins and enzymes that you need in order to separate this actual kind of chromosomes into the separate daughter cells. But you're getting the cytoplasm bigger, you're increasing your enzymes, and you are getting ready to start dividing these cells. Then what happens 5:05 is we're going to take the cell, we're going to start dividing the actual genetic material. And when we divide the genetic material into two identical daughter cells, that is when we have what's called the Mphase. All right? So this is the Mphase. Now, the Mphase is also referred to as mitosis. Mitosis consists of a couple different parts. So you can often times remember this via what's called PMAT right and so we call this proase right then we have what's called metaphase then we have anaphase and lastly there is tilophase and again we talk about this more in the cell cycle video but for simplicity sake all that we do in the prophase is we start kind of condensing down this genetic material we condense it down. And then also you start to begin to see these things called, and I'm going to represent them with circles and maybe some lines coming off of them. Your centrosomes, which are going to be where the motic spindles originate from. They 6:06 start kind of going to the opposite poles here. Then in metaphase, what happens is this chromatin is pretty condensed. And then you start noticing that these mitoic spindles are moving and then your chromosomes are lined up in this nice kind of like equatorial plate and we call that metaphase. Then you have the point here where the motic spindles are starting to depolymerize and they're separating these sister chromatids into different cells. And then we get into tilophase where we're literally starting to cleave the cells in half. This is the different parts. Now, the reason why I'm stressing on all of this is when we give anti-neoplastic agents, they can act in different parts of the cell cycle. So, we can have drugs inhibit the cell when it's in the Sphase. We can have drugs inhibit the cell when it's in the G2 phase. We can have it inhibit when it's in metaphase and anaphase. And that's 7:07 the important point. So, we'll talk about this a lot, but a lot of the drugs, they tend to really have the most profound effect in the Sphase when the DNA is replicating. We have some of them that work in the G2 phase as the DNA is replicated, but we're getting the actual cell really ready to separate. And then metaphase and anaphase tend to be some heavily involved areas. So this is what I want you guys to understand because now what we'll do is we now build up a point here where I can say which drugs are anti-neoplastic chemotherapeutic agents that are cell cycle specific meaning it involves one of these phases and which ones are cell cycle non-specific meaning that they can affect any point including the G knot because often times when we talk about and this is one of the key basics of chemotherapy when you talk about cancer cells. They have a high growth fraction. They replicate like bunnies. When you give chemotherrapeutic agents, they have there's something called the logill hypothesis. Write this down. The log 8:09 kill hypothesis essentially says when you give a chemotherapeutic agent, it causes a constant fraction of cells to die off with every round of chemotherapy. It's not a constant number of cells. It's a constant fraction of cells. And that type of cell that is usually getting killed by chemotherapeutic agents are highly replicating cells. That's what chemo goes after. What are the most highly replicating cells in our body? Think about it. If you have cancer, it's cancer cells. What's the one that if we didn't have this thing proliferate, we would just we would see you'd see the person's bones and muscles and fat. Your epidermis, so your epithelial tissue, so your that makes your skin and all of your mucosal linings. So, you ever notice how when people take chemotherapeutic agents, what happens to their to their parts of their skin? What what actually makes up part of the what's actually technically skin? Hair. They have hair loss, right? Another thing, it affects their mucosa. So, they can develop mucusitis. They can have a lot of GI problems. You ever notice some common symptoms of chemotherapy agents? Nausea, vomiting, diarrhea, abdominal 9:12 pain. The other thing that it also affects is your bone marrow. your bone marrow is constantly replicating and making different types of cells. If I give chemotherrapeutic agents, what would it affect? It would affect those. And so sometimes they can have decreased numbers of white blood cells, red blood cells, platelet. So panytoenia. And so that's why it's really important when we talk about these drugs, you should have cell cycle specific. They're affecting cells at different parts of the cell cycle or cell cycle non-specific. They can affect it at any stage. And that includes the ones who are in the resting state. That's your cell cycle non-specific. Okay, now we've kind of built up an idea that we know the different phases that the cell can be in. And so whenever you have a cancer cell, these cancer cells are scary, man, because they can basically develop mutations that allow for them to keep going through the cell cycle and replicating and replicating and replicating, right? So they develop mutations for whatever reason. Those mutations allow for them to increase the proliferative genes and shut down the tumor suppressor genes. The other thing 10:13 that comes into this is now talking a little bit about how we regulate the cell cycle. This is really critical. So let's say for example here we have the DNA inside of a cell. There is different ways that when we kind of go through these phases and this is a critical checkpoint. Usually when you go from the G1 phase into the Sphase, there's a checkpoint there. And there's a very special set of enzymes that kind of control this step. And these enzymes are really important. So let's write these down. This one is actually they're a it's kind of a group. So you have cycl D and then you have these CDKs which are cycl dependent kinases. So you can't have the CDKs without having the cycl D. But usually this is going to be CDK 4 and six. All right, I do want you to remember that. The other thing that you'll have is this red protein. This is called retinino blastoma protein. We're going to write that as RB. And then the green one is called E2F. Now, what normally happens is that this is influenced by a bunch of different upstream pathways. And so, what CDK4 and 6 is supposed to do is it's supposed to 11:14 put some phosphorates, phosphate groups onto retinol. So, it's supposed to basically it's supposed to kind of add phosphates. Let's say that I add some phosphates here. When you add phosphates to the retininoblastoma protein, guess what it does? It lets go of E2F. So, it basically once the phosphates bind to it, boom, E2F gets released. So now we're going to kind of dispense the E2F. So here E2F was bound. Now I need to come over here for a second, guys. Grab my green marker. This is going to be my free E2F. So now I have free E2F and this is actually going to start moving over and then what it's going to do is it's going to act on kind of special different enzymes. And let's say that it acts on some special enzymes. and when it uh I'm sorry special genes and it basically it's going to stimulate genes and let's say that these genes want to kind of push the cell into the proliferative state it wants to push the cell to go from here to here that's what it can do right so we're going to activate different types of genes to 12:14 really help to stimulate this process that's how this works so CDK4 and 6 phospholate retinoplasto release E2F E2F activates particular genes because E2F is a transcription factor when it activates these genes it then says Go ahead cell, continue into the actual cell cycle. That's pretty cool, right? And so this is a very key regulatory point. The key thing behind this is that there's a lot of upstream things that are influencing this. All right? So if a cell wants to go through that cell cycle, it needs these different points where we can say, "Okay, you're good." Here's a couple different things. One is we can have something called a well there are different types but we have what's called a uh usually it's a tyrrosine kynise receptor. So you have different types of tyrosine kynise receptors, right? So many different types, right? And so usually what happens with these with these tyrroscen kinase receptors is you have some type 13:14 of molecule, a lian of sort that will bind onto these. Usually these are some sort of growth factor. That's usually the key. There's some sort of growth factor. And when you have this growth factor, what it'll do is it'll bind on to these receptors. And there's a couple different types. I mean, we'll list them. One of them is called EGFR. The other one's called ALK. So, you have one called EGFR. You have another one called ALK, right? And there's even um not even membrane bound ones. You have another one too, which is actually inside the cell. It's kind of like a tyrroscen kinus, but it's a non-membranebound one. So, it's it's really an interesting one. And this is called a BCR aable. So this is called BCR aable tyrrosine kynise. All right. And these are all like special enzyatic like receptors. This one is membrane bound. This one is kind of like in the cytoplasm. Either way, when you have something like this happen, like let's say that you have a 14:15 growth factor hit the tyrrosen kynise receptors, it can trigger intracellular pathways. Usually there's a couple different pathways and I don't want to go too crazy but they can increase the presence of of some different kind of intracellular processes called like PI3K AKT. It can do another one which is actually really important. It's called the RAZ pathway. And so we actually call this the MAP kynise pathway which is basically you increase the activation of RAZ. RAZ then leads to the activation of Raph. Raph leads to the activation of mech and mech is usually going to lead to the map kynise. Either way, these are intracellular processes. And the other thing is they can increase the presence of what's called stat, which is a signal transducer of activated transcription. Either way, growth factors bind to these receptors. They increase this pathway. This pathway then does what? It then goes and increases the activity of specific processes like what? Well, it can it can lead to some downstream processes. So, here's CDK4 and six, 15:16 right? It's heavily influenced. It may lead to these downstream processes that lead to a stimulation of CDK4 and six. And so if I stimulate CDK4 and six, what will it do? Phosphollein blastto. What will that do to E2F? Let go of E2F. If I let go of E2F, that'll activate specific genes. These genes will then push that cell to go through the cell cycle and replicate. So you see how growth factors can do that. we can come up with drugs to target these to target the eGFR receptor to target uh the alk component of the tyrrosen kinus. So we can do that. The other thing is the BCR aable you can have specific things particularly ATP bounded sites and what you can do is you can block this little component here because BCR aable if it gets activated when it's stimulated it can also trigger these pathways the same kind of thing and so if I have a drug that could bind into the ATP binding site of this I could inhibit it and I could shut down these pathways and shut down this going from G1 to the S-phase that's cool right the other thing we 16:16 have not only do we have these tyrosin kynise receptors But we have other receptors too. So for example, we also have ones called Jonis kynise. So these are usually called your Jack 2 receptors. And what happens is these usually combined some type of growth factor. Same concept. Let's actually draw these kind of like coming over here as well. So you have growth factors binding here onto this. And you have growth factors coming over here and binding onto this. Guess what? They can do similar things. The primary one that they tend to lead to the activation of is stat. Either way, same downstream process. So if I had a drug that could block this, I could potentially shut down this kind of cell proliferation. That's why we usually give this kind of drug in people who have milo proliferative disorders. We give a lot of these drugs, particularly the EGFR and the alkquins. We give these things in like lung cancer. Um we can also use these a lot in certain types of um you know hematic malignancies especially things like for this one CML, but we'll we'll talk about that. Another one is you can have something called a her two. 17:17 All right. So a her two it's like a human epidermal receptor and this one can also be bound by different types of lians. And when that leads to this process again it leads to the same thing. It can and we'll just kind of write this down here. We'll do the same thing. But if you activate this receptor guess what you're doing you're increasing the pi key uh pi3k akt increasing the map kynise and increasing the stat signaling. So PI3 K AKT you're increasing the map kynise pathway and you're increasing the stat pathway. Either way all of these things are leading to that downstream influence on CDK4 and six. So if I gave a drug that could block this receptor I may shut down this pathway and that's a concept there. Another thing that I also want you guys to understand is we can have receptors that are present inside of the cell inside. So for example, you can have different types of receptors. This could be an estrogen receptor, right? This could be I mean you have 18:18 other processes too. You it could be an androgen receptor. And if these things come inside and bind to these receptors, guess what? They can also lead to this process here. And so what I'll do is I'll kind of bring this one here and I'll join in. I'll get I'll make this a little bit smaller. We we'll squeeze this one in here. But it's the same concept. If you have estrogen or androgens binding onto these receptors, once you do that, this is going to lead to them activating the CDK4 and six. So this is why I'm trying to tell you this. If a patient has scenarios where they have abnormalities or mutations in the tyrroscen kinus receptors, abnormalities in their jack 2 receptors, abnormalities in the her too, abnormalities in the estrogen and receptors or maybe in pathways that influence that because you know there's other ways you have other enzymes like aromatases which are also supposed to convert estrogen into androgen. There's 19:20 so many different types of targets. The only the big thing is that you have all these upstream pathways that are leading down to this pathway and this really helps to drive the cell cycle. If I could come up with ways of targeting all of these different steps, I could shut down a lot of the cell proliferation. That's what I need you guys to understand is if all of these are really coming downstream and influencing this, if I come up with drugs to target this, this this this I provide a massive benefit. And guess what? I can even have drugs that influence these pathways. So that's what I'm trying to get you guys introduced to is understanding the basic pathway and how we can bring drugs in to target this. And eventually all they're going to do is shut down CDK46, shut down phosphorilation of retinol blastoma, shut down E2F, and shut down the initiation of that cell cycle. So if we think about this again, kind of giving you a little recap, there's a couple different types of receptors I want you 20:20 guys to know. I think a really really important one is the tyrroscen kinise. Do not forget these. So these are your tyrroscen kinus and these could be the membrane bound but they could also be the constituent enzymes like the BCR aable inside of the cell. Please don't forget that the other one is going to be the jack 2. The other one is called the her two and then the last one is going to be your steroid receptors. These are your steroid receptors. Usually this is for things like estrogen, androgens etc. All right. pathways that are usually downstream from this is going to be things like PI3 KT and some of you who are actually really into your kind of like cell biology you know that this will lead to the increased production of mTor which we have certain chemotherapeutic agents as well you have we'll write this one out the RAZ raph mech this is usually via the map kynise pathway and then lastly you have the stat signaling right basically All of 21:23 these in some way, shape or form increase these pathways. I can shut down this, this, this, this, and I can shut down all of these. The ones that usually are the most talked about for the step two is going to be this one. And then lastly, we have a lot of enzymes that are controlling in this process, but the key ones that I wanted you guys to really know that influences this is what? CDK4 and CDK6. There's a reason I'm writing all of these down. Um, and the reason why is because when we start talking about each one of these drugs, we're going to have drugs that influence the S-phase. We're going to have drugs that influence metaphase, anaphase, G2 phase. We're going to talk about those cell cycle specific, cell cycle non-specific. When we get into the drugs that influence cell cycle regulation, we're going to have tyrroscen kinus inhibitors, jack inhibitors, monoconal antibodies. We're going to have different hormonal therapies. We're going to have we're not going to talk about these, but we're going to talk about some specific types of drugs that work again in this pathway. the RAZ, RAFP, mech, map MAP, Kynise pathway. And then again, we're 22:23 going to have drugs that are targeting the CDK4 and six. All right, now that we've done this, there's one more thing that I got to talk about before we really start getting into these drugs, and that's guess what? These cancer cells, not only do they gain the capacity to have mutations and replicate uncontrollingly or they have things that are driving them to really go and undergo a lot of cell replication, but we have to have ways of controlling these cancer cells. And we have immune surveillance that we're going to talk about next. All right. So, now we're going to move into the next part. So, this is going to be the immune evasion. So, it may seem like this is very random. I promise there's a there's a a method behind the madness, if you will. Um, so the reason why I'm kind of doing this little kind of extra piece is because there's a lot of newer drugs that we're using as anti-neoplastic agents that can really essentially activate our immune system, turn the tea cells on to start kind of fighting some of these cancers for us. One of the interesting things here is that whenever cancer cells, not only do they gain this ability to, you know, develop mutations 23:24 and then because of those mutations, they allow for alterations in their cell cycle. And so because of that they may increase protoolco genes which allows for them to proliferate shut down tumor suppressor genes which again evades apoptosis so they can replicate and then they don't die. On top of that, they're also really really kind of smart in the sense that they can potentially evade the immune system. And so they can do that by increasing the expression of specific lians on their surface that shuts down tea cells or they can increase the expression of certain lians on the T-C cell which then makes it where it can't interact with antigen presenting cells to activate them. So they're kind of interesting in that sense. And then the other thing is that cancer cells also they want to steal all of the blood supply so they can get oxygen, nutrients, they can grow, they can metastasize and so they have a lot of angioenic mechanisms that are involved. So when we talk about cancer cells and tea cells, let's kind of take a look here. There's different receptors on their surface that need to kind of interact essentially. And so one on the cancer cell, usually they express 24:23 something called a major hystocompatibility complex, usually with some sort of like antigen on the surface. In order for that to really take place, you need to have the T- cell receptor interact with the antigen and then usually some type of cluster differentiation protein of some sort. We'll just kind of represent this with like let's just use for right now we'll use this baby blue color. So they usually have some type of cluster differentiation protein which interacts with the MHC. Right? Now the other thing here is that on the T- cell expresses something called PD1. So it expresses something called PD1. Now usually PD1 has to interact it usually will interact with something called PDL1 which is the liand and that's usually something that cancer cells are smart. They will increase their expression of PDL1. If they increase their expression of PDL1 that allows for this interaction to take place. So then what you're going to do is you're going to allow for this interaction to occur. If you stimulate this interaction, guess what it does to the T- cell? It tells the T- cell, hey, 25:24 go ahead and turn off buddy. you don't need to do anything to me. And it kind of shuts the TE-C cells activity from killing this cancer cell down. And so that's kind of interesting is it can basically in a way it can turn that TE-C cell off. So let's say here I'll just kind of write it like this. It turns off the T- cell. All right. The next concept is that cancer cells also are interesting because what they can do is they can in some way signal to te- cells and they can cause these te- cells to increase their expression of another type of molecule. So again let's say here we have a T- cell here you have an antigen presenting cell right this could be a macrofase dendritic cell it could be a bunch of them on their surface of the T- cell you have what's called a what a T- cell receptor here on the antigen presenting cells they express MHC's usually this is a one this is a two there's an antigen and then again technically for this true interaction to take place you need a cluster differentiation now in order for this T- cell to be 26:24 activated it needs not just this interaction between MH HC and CD TCR and antigen it needs co-stimulation that co-stimulation is done via something called B7 on the antigen presenting cell and CD28 on the T- cell. Now what's interesting is that these cancer cells will tell the TE-C cell to increase the expression of another molecule and this molecule is called CTA4. Now why is this a problem? When you have CTLA4 and you're increasing the expression of it, it beats out the interaction between CD28 and B7. That's what ends up happening. So then what ends up happening here is if I kind of like move this, let's say that this guy becomes so more like a strong affinity, it essentially will move this CD28 out of the way and then this CTLA4, guess 27:26 what it's going to do? It's going to come over here and it's going to bind in. That's one of the benefits here. So here's CD28 and here, my friends, is CT4. And now these can interact. When this right here occurs, this interaction occurs, it basically turns the T- cell off. So now if I do this, I turn off the T- cell. And if I turn off the T- cell, can it go after the cancer cells? No. Now you're probably like, okay, what's the point of all of this? I I get it. We're going to kind of make come up with drugs, right? Yeah. If I can have a way of inhibiting CTLA4 or inhibiting these two, maybe PD1 or PDL1, I could potentially do what? Turn the T- cell on to kill the cancer cells. Turn the T- cell on to kill the cancer cells. That's what we'll talk about eventually when we get into those drugs. 28:27 And we'll talk about these are called your commonly they're referred to as your immune checkpoint inhibitors, which are like types of monoconal antibodies. All right. The other thing that's really important about cancer is again the angiogenic effect. Blood flow is key. You know cancer cells they need oxygen they need nutrients and they require a lot more because of how heavy their proliferation process is. They need a lot of these metabolic processes to be driven by oxygen and that needs to be present to make ATP. And so because of that cancer cells are smart. And what they do is they secrete a chemical called vef. Right? So, VEGF is vascular endothelial growth factor, right? So, that's what it's called. It's called vascular endothelial growth factor. Now, vascular endothelial growth factor will basically bind onto these receptors. And these are called your veg F receptors. What will happen is is when veg binds on to these receptors, where is it present? That's the first question we should ask. 29:27 Do you notice where this is? This is the blood vessel, but what part of the blood vessel? The endothelial cells. And so what it does is it activates the endothelial cells to undergo replication. And when they undergo replication, it goes from this vessel to this vessel. Do you see all these sprouts that came off? Because the endothelial cells, they started sprouting off and they make more vessels. What's this called? Angioenesis. So what it does is it increases, let's actually write this here. It increases angioenesis, which is what? Making more blood vessels. Now, if I make more blood vessels, what's the benefit of that, my friends? I'm going to increase oxygen delivery and nutrient delivery to the cancer cells. So, therefore, you get increased O2 delivery. If I get increased oxygen delivery, nutrients delivery, what's going to happen to these cancer cells? They're going to grow. 30:28 And if these cancer cells grow, my friend, oh boy, that's when we get some problems. So if we had a way of be able to come up with drugs to target these, especially VF, I may be able to shut down the edgeogenic process and shut down the oxygen delivery and shut down the cell growth. That's kind of really interesting. So at this point, we've talked a lot about the basic physiology. What I now want to do is is let's take it one step forward and say let's integrate the drugs into these basic physiological processes and see how we can influence these processes. See how we can shut it down. And I think it'll help us to remember these things a little bit easier. All right. So let's move on now to the cell cycle inhibitor. So we talked about the cell cycle in great detail, right? And again it's really it's it's it's pretty simple, right? When you take and you you actually take a cell who you've duplicated the number of chromosomes you want to separate those out to your daughter cells right and so these should have the same number of chromosomes and again that was denoted as the Mphase that was your mitosis that was the 31:29 proase the metaphase the anaphase the tilophase right then if we take one of these cells it just got duplicated it's going to want to get duplicated again so what does it have to go through well it can either go into a resting state or it can start growing and getting ready making enzymes proteins that we need to replicate the DNA A. So that's what we do. We make more organels. We make more proteins. And then we get ready to duplicate the DNA. That's when we go into the Sphase. Once we've duplicated the DNA, we want to start making more proteins, more enzymes, increasing the cytoplasm size so that we can split this equally between the two cells. That's when we go into the G2 phase. We talked about this, right? With the cell cycle. There's drugs that are targeting specific points of the cell cycle. When we have cancer cells, we want ones that are constantly going through the cycle. We don't want a lot of the cells to be in this resting state. All right, that's the important thing. And so we have cell cycle specific. So what does that mean? Meaning that they target G1, S, G2, Mphase. That's where they're working. G1, they're working particularly in the 32:29 Sphase. They're working in the G2 phase. They're working somewhere within the Mphase, right? That's where they're working. Whereas cell cycle non-specific, they can occur anywhere. Usually when we say cell cycle specific, we have S-phase inhibitors, G2 phase inhibitors, Mphase inhibitors. When we talk about cell cycle non-specific, this could occur, dude, you could even do it in the resting state. It could be G1 and G2. I could have it occurring in the Sphase and the Mphase. So, this is not specific. It's not a specific area in the cell cycle that they're inhibiting. That's the difference between these two. And this is the key one is that the cell cycle non-specific can occur in that resting state that G not phase whereas this it's not going to really affect the G knot and usually it's going to be one specific phase so for example let's kind of make sense of this we have the Sphase this is a really important one so the S-phase inhibitors right so we'll talk about it in this sense but we'll get 33:29 into more detail and how exactly they inhibit the Sphase but when we talk about Sphase inhibitors we have a couple different drug categories The big group, and we'll talk about a couple of them, is going to be your anti- metabolites. These are a heavy class of drugs. And when we talk about these, we're just kind of introducing it a little bit. We're not going to go in crazy detail. How they really work is that they inhibit nucleotide synthesis. So, they may inhibit the formation of purines, perimeitine nucleotides. They may inhibit their incorporation into DNA. They may inhibit some of the enzymes that are needed to make the DNA from those nucleotides. That's how they are working. Another group of drugs that also work within the S-phase. And again, Sphase is when the DNA is replicating. You're making more DNA. Topo isomeases come into play. You guys remember that from cell biology, right? We have topoases. Basically, you have the DNA replication for downstream. Upstream from that you have an enzyme because you have what's called what? You have what's called torsional stress. And so whenever you 34:31 have these torsional stress, what happens is you have super coils and then topoisome are supposed to come and actually cut the DNA, let it unwind, reduce that torsional stress and then connect it back together. What if I had a drug that could cut and then let it unwind and never glue it back together? The thing would unwind, unwind, unwind, and eventually you wouldn't be able to allow for the DNA to completely like heal and the replication forks would be all jacked up. That's going to be topoisomease inhibitors. And there's one and two. This is the one that only works in Sphase. So topoisomease one works in the Sphase. Therefore, topism 2 works in a different one. And we're going to talk about that. Usually it's the G2 phase. So let's move on to the next one. The G2 phase inhibitors. They only work particularly in this phase. Well, again, I kind of already hinted at one of them, and that's going to be your topoase 2 inhibitors. There's another drug and this is a part of your anti-tumor antibiotics which we'll talk 35:32 about. So topo 2 inhibitors and then the other one is going to be bleomy. Now this is an anti-tumor antibiotic. We'll talk about that a little bit later. All right. The next one is Mphase. So Mphase inhibitors which is going to be working in mitosis. So Mphase inhibitors, they're primarily affecting things like your metaphase and anaphase. And so what they're doing is they're inhibiting particularly the microtubules from polymerizing and depolymerizing. And this is going to be your microtubial inhibitors. And we'll talk about these groups a little bit later as well. So microtubial inhibitors. Now the last one I'm hesitant to kind of include because technically it's not really a phase, it's more of a checkpoint. So usually you have something called checkpoints. And there's a really important checkpoint which occurs right here kind of before we go into the Sphase. This is called the G1 um Sphase checkpoint. And so when we talk about this G1 Sphase 36:37 checkpoint inhibitors, there's different cycle dependent kinases that regulate the cell cycle. That's why I want to talk about them more over there. But we had a specific enzyme that's really involved in this process. It's not upstream. No kind of upstream involvement. I'm talking about only direct and that's the cycl dependent kinases. So technically we could say that a CDK4 and six inhibitor could potentially affect the cell cycle specifically around that checkpoint level. But I'm going to talk about that a little bit more over in the cell regulation processes. All right, but for right now we're just going to kind of slowly kind of integrate it here. But be aware we will talk about this more so when we get into the cell regulation. All right, cool. So here's the drugs that specifically inhibit parts of the cell cycle. These could occur at any at any phase. It's not specific, dude. It's just not. So because of that, we're going to talk about these. This is usually going to be I'd say two primary categories. One is called your anti-tumor 37:38 antibiotics. So your anti-tumor anti-otics, you're like, wait, what? What the heck? Anti-tumor antibiotics. These are weird. These are going to be some ones that we use a lot called docar rubison, donor rubicon. Um we also use dactenomy, mitoc and bleomy funny enough as an anti-tumor antibiotic but it's the only one that is specific. All these other ones are usually non-specific. The other one are called your alkalating agents and these have different kinds of groups that we'll talk about as well. This is going to be things like your nitrogen mustards like cycloposomide, iosomide, melphan. We'll talk about your other ones which are your platinum compounds cis platin carboplatin as well but these are going to be very very particular in that they do not have a very specific cell cycle that they influence. Now, we'll talk about this as well a little bit later, but when we think about the process of how when we take something and we form something like proteins, we go through this very consistent sequence where we start off with usually things 38:39 like nitrogenous bases, right? So, this could be things like your purines um or like pyramidines, right? In this case, we're using something like purines. Then the purines are making something called ribo nucleotides. So basically we're taking the nitrogenous base adding on a carbohydrate group and a phosphate group and then we convert that and we actually kind of dehydrate it. So then we make something called a deoxy ribbo nucleotide and then we take these deoxy ribboucleotides right which is usually it's a form of we take this things like adenosine thymine cytosine all of those guys and we're incorporating them into this structure and then adding it into the DNA and so this is how we generate things like DNA and then DNA we can translate and we can turn this into RNA and then RNA we can do I'm sorry we can transcribe DNA make RNA and we can translate RNA to make proteins. So we have drugs that can work along 39:42 this process. So you can think about them as being cell cycle specific or non-specific, but you can also think about this mechanism as well because we're going to have a bunch of different drugs that are influencing all of these different stages. Let's start off with talking about the anti- metabolites first. So when we talk about anti metabolites, they're really going to be affecting I'd say a couple of those stages up there. They're going to be affecting going from like the nitrogenous bases to the nucleotides. So ribo going from ribo to deoxy going from deoxy to DNA. So we have a couple different groups. One is called folate antagonist. Now folate antagonist really consists of one drug and this is called methotate. All right, this is called methtoresate. a little intro into this process that occurs inside of our cells. Let's say here's a cell. We need this cell to start incorporating nucleotides into the DNA or to make DNA. So, we want to make some DNA for this cell so that we can actually help to make another cell. Well, we need a molecule called folate. 40:44 Folate is pretty crucial. And so, what happens is folate gets brought into the cell and then what happens is eventually it gets converted into something called dihydroofolate. And then dihydroofolate can be converted into another molecule called tetrahydropholate. Right? So we're going to convert dihydropholate into tetrahydropholate. Then tetrahydroofolate gets converted into another molecule called 510methylene. 510methylene tetrahydroofolate. Now here's the important thing here. When 510 methylene tetrahydroofolate is formed, it can go a couple different processes. But the important one is that it can actually get converted back into dihydroofolate. When that happens, this interaction creates more of a donation effect to help us make something else. And that's something else that we're going to make is we're going to take a deoxy ribbou a deoxy ribboucleotide 41:44 called DUMP which is basically that kind of deoxy form of uricil and convert it into dtmp which is basically the deoxyiform of that thymine nucleotide. Guess what this is going to do? This is going to help me to make thyodine. Thymodine is a very precious nucleotide that we need to be incorporated to make DNA. So this is going to help us to make the DNA. Now I have basically a couple different reactions here. Let's use one enzyme here. This is regulated. This step here is regulated by an enzyme called thyolate synthace. All right. I'm going to abbreviate this TSA centase. There's another enzyme. Let's do this one. We'll do a blue blue color again. This is called This one is called dihydroofolate reductase. What is this enzyme called? This is called dihydropholate reductase enzyme. Now the drug methotate 42:47 which is kind of cool here. We're going to abbreviate this MTX. MTX is going to work by it gets taken into the cell and inhibits this enzyme. If you inhibit the dihydropholate reductase, can you convert this reaction? No. If I can't convert this reaction, what happens to my tetrahydropholate levels? They drop. What happens to my 510 methylene tetrafolate levels? They drop. Can I now even if I have this in excess and I have this enzyme, can I now convert this into this DTMP? No. So what happens to this process? It gets shut down. Now I have less of the thymodine. If I have less of the thymine, can I make the DNA? There's a decrease in DNA synthesis. So now I shut down that DNA synthesis. Oh man, that's cool, right? Another thing here is tetrahydroofolate is also used to make other nucleotides. We're not going to talk about this pathway. We talked about in the nucleotide metabolism video in our biochemistry playlist. Go watch it there. But this can also be used to 43:49 make things like purines. And so if we have less of this tetrahydroofolate, we theoretically shut down the synthesis of purines as well. And purines, this is a perramdine, right? So thymine, usually the thyodine is a perramdine. Purines, they're also going to be involved to make DNA and so that'll shut down your DNA synthesis as well. But the primary one I want you to remember is thyodine. So when we give drugs like methtoate, it's inhibiting this enzyme and shutting down this p process. Now another thing that's really really important here is the perramdine antagonist. So now we got to talk about the nucleotides. So we kind of introduced it a little bit. Perramdines are going to be the single ring. So when you think about that that's kind of I just remember it's the six ring structure, right? Purines are the double ring structures. All right. So perramdines this is usually going to be things like your thymine, your uricil um and then your your your cytosine, right? Whereas your purines are going to 44:50 be your adenosine, your guanine. It's going to be those guys. Now I want to have specific drugs that can inhibit the formation of perramdines and their incorporation into the DNA. So there's a couple different drugs. One of those drugs is called 5FU. No FU. No, I'm just kidding. So five floral. Another one is called um citabine. So it's called citerabine. And then one more that's kind of an important one is called gymcytoine. So jimcytoine. So these are all different types of drugs that we can utilize as perramitine antagonist. And all I want you to think about is for the most part some of these act like a nucleotide but they're not a functional nucleotide which is kind of interesting. All right let's go over 5FU first. So 5FU is kind of it kind of goes off this pathway already. So this is kind of nice. We take something like folate and folate gets brought into the cell. 45:50 When it gets brought into the cell, what does it get converted into? Dihydropholate. Dihydropholate gets converted into tetrahydropholate. Tetrahydropholate into 510 methylene tetrahydropholate. 510 methylene back to dihydropholate. And then we use a molecule called what? DU NP. So we use something called DU MP and convert this into DTM and this is utilized to make something like D N A right. So now with that being the case we have a couple different enzymes involved here. So this one here is called dihydropholate reductase. We talked about this one. What's this one here? The thymito centase. This is called the thyolate centase. Guess what 5FU does? The 5FU shuts down thyolate centase. So that's what 5FU is going to do. It's going to get inside of the cell, 46:51 right? And when it gets in here, oh, I got to bring this guy somewhere around here somehow. We'll bring it here. There you go. It's going to inhibit thyolate synthes. And so if it inhibits thyolate synthes, you won't allow for this interaction to occur. And if you can't allow for this interaction to occur, DTMP levels drop. If DTMP levels drop, then I don't have the DTMP present to be able to incorporate into the DNA as a nucleotide. And what happens to DNA synthesis? I decrease DNA synthesis. So with this reaction that we kind of talked about here, it's really really crucial to remember that if you're inhibiting this enzyme thymitoase, it's 5FU. If you're inhibiting this enzyme in this similar process, dihydropholate reductase, it's methtoresate. Either way, both of them are shutting down thyodine synthesis and that's shutting down DNA synthesis. This is an important thing to remember because oftent times we use drugs like uh luccovorin or felinic acid and that actually can it's 47:53 interesting because it can be a rescue drug in methtoresate but enhance the effect in 5FU and that's just a little kind of thing to add on there to note but again difference in the mechanism is dependent upon the enzyme but the end result is the same. All right, citabine and gimcyine are kind of cool when we talk about these what happens with these and we can kind of we'll group them together. So citarabine and then jimcytoine what happens with these is that these kind of basically when when you ingest them they're called nucleioide analoges. Nucleioides are basically you have a ribbo sugar and you have the nitrogenous base but you don't have a phosphate group. And so that's how you ingest them. Once they get into the body they get phosphorolated and then they generate kind of things that look like nucleotides. And so that's what happens when they get into your actual cells. They get brought into the cell and I don't want you to know these if you're really hardcore in biochemistry. Yes. 48:55 Caiterine technically gets broken into what's called a CTP. gym cytoine technically gets broken into something called DF DCTP. All I want you to know is is that they are nucleioide analoges, right? And so they're going to be nucleioide analoges. All that means is is they are going to have the ribbo sugar. They're going to have the nitrogenous base. They're not going to have the phosphate group that gets added on and they make these things that look like nucleotides. Dude, it looks like a nucleotide. And so what happens is here's this enzyme DNA polymerase. DNA polymerase is moving down. It's reading the the nucleotides. All right, it's A. All right, cool. Let me add on a T. Here's a G. Oh, let me add on a C. And then what it does is it grabs in its back pocket and it grabs these. And these tend to look like they tend to look like cytosine or cytoine triphosphates. That's kind of what they look like. So they're CTP let's say lookalikes or we'll call them mimics essentially. I think that's the best way of saying it is that they're they're 49:56 essentially their CTP mimics. All right, so cytoine triphosphate mimics. So what happens is whenever the DNA pulymerase goes in its back pocket to grab a cytoine because it's got a guanine over here that it wants to pair with, it adds this one on. And when it adds it on, there's no point where the next nucleotide can attach. And so it terminates the DNA uh elongation process. And so when you incorporate these in, essentially what it does is it inhibits DNA elongation. That's really what I want you to think about. It inhibits DNA elongation. So it's kind of like a termination point elongation. The other thing is is that some of these analoges, if you have too many of them, DNA polymerase is regulated by the number of like nucleotides that it has around it. So if you have enough of these, guess what they could do? They can inhibit the DNA polymerase, bro. So tell me that's not cool, too. So they can inhibit the DNA polymerase. If I inhibit DNA polymerase, doesn't matter 50:57 if I have nucleotides present. I won't be able to elongate that process. So again, when these get into the actual cell, they get phosphorolated. They look like cytoodine triphosphate. Here's the DNA polymerase, right? It can be inhibited by these, but on top of let's say it's not inhibited. It's reading, it's reading, it's reading, and it's adding on the complimentary base. But then let's say it gets to this one, you add on. Let's let's just keep it going. Let's say, oh, I got the the blue one. I'm going to add the red. Okay, blue one. I'm going to add the red. And then now it grabs on and it grabs one of these CTP mimics and it adds this one on. That's where it ends. It terminates right there. You can't add anymore. So you don't have the next thing to add. And that kind of inhibits that DNA process from elongating and it terminates the DNA replication process. So that's what I want you to remember for these guys. Now gymcytoine is interesting because at high concentrations it can even inhibit another process. There's another enzyme we talk about up there. It's called riboucleotide reductase. So riboucleotide reductase is an enzyme that converts a ribboucleotide into a 51:58 deoxy ribboucleotide. And Jim cytoine at high concentrations can inhibit that enzyme. All right, that's the primitine antagonist. What about the purine antagonist? So for the purine antagonist this is your double ring structures and so this is going to be that 6 + 5 this is going to be things like the adinine the guanine right with these when we talk about things that are acting like that or mimicking those types of triphosphates essentially we have things like six mercaptopine as a thioprene these are this is a really powerful drug category and these also can act as amunosuppressants as well and then we'll add this next one And and these are commonly used as well. But this is called cladrabine and fluorabine. And these are interesting because they really work really well in uh certain types of leukemia like hairy cell leukemia and all. So really really interesting drugs here. I think the 52:59 reason why is if you come across this in your kind of like your textbooks especially like the step one I'd like to talk about this. There's something called adenosine diaminise. And adenosine daminase is really interesting because it's present in lymphocytes and sometimes patients can have u you know resistance to adenosine daminase. This two drugs have ADA resistance. So they don't get affected by adenosine diaminise and because of that they can still produce a pretty profound effect in lymphocytes and kind of prevent their proliferation. So that's what's important about these is that these are ADA resistant adenosine diaminise resistant. All right, let's talk about this one here. So, aathioprne is essentially kind of like it's a it's really it's the prorug of six more capne. So, when you give a drug like aithopene, right? Let's say that you give a drug like a thioprene. You ingest it. It gets taken into the body, it actually gets broken down into six more captopine. So, that's really what they're kind of the same thing. When you when you ingest this, it gets broken down to six more caperine. When six more capabin gets into the body, what happens 54:01 is is it gets acted on by an enzyme called HGPRT. All right? So there's an enzyme here called HGPRT. And that HGPRT is going to convert six more capine into what's called six thio. Six style IMP is like a weird little son of a gun. It's basically kind of a molecule that can shut down so many different types of pathways. It's kind of crazy to be honest with you. It can shut down essentially a couple different things. One is it's going to decrease your PRP synthetase. You know there's an enzyme that helps you to take PRP and glycine and make something called imp. That's one thing. Another thing is it also inhibits another enzyme called adenosine diaminise and that's basically responsible for converting adenosine and deoxyenazine into imp deoxyimp. All 55:04 right. So essentially what's going to happen is is it's going to decrease a molecule called imp.MP is important and the reason why imp is important is because imp is basically a a precursor for making something called a M and GM. right? Which is you're adding uh monofh phosphate your guanium monof phosphate which eventually these need to get turned into deoxyucleotides and then incorporated into the DNA. So eventually they're converted into deoxyucleides but this is supposed to make these. So if you give this drug it inhibits enzymes that help to make IMP. So if you drop the imp levels you drop the AM you drop the GMP. And if you drop these levels, guess what? You drop the synthesis of DNA because you need these once they get converted into the deoxyucleotide form. You need these to make DNA. That's one of the things I 56:05 want you guys to understand here. All right. The other thing here is that these can al also this thio impact as a nucleotide analog. The same thing like this. So it can act like a mimic. So it can act like a mimic. Basically it can act as a we call this a um a nucleio side analog and these are basically mimics of certain types of triphosphates or deoxyucleotides. So that's one of the big things here is that it's also going to act as a nucleotide analog which is going to shut down the DNA elongation and maybe even inhibit what's this beautiful blue enzyme here DNA polymerase. All right. So as a theoprene sixmer caperine gets taken into the by the body converted into six thou imp works on a couple different enzymes adenosine daminase PRP synthetase adenolosuxinate uh dehydrogenase and decreases imp levels. Less imps less of these eventual 57:07 deoxyucleides to make DNA and also can act as a nucleotide analog to get incorporated into the DNA and terminate DNA elongation. Now cladribene and fluorabine are nucleotide analoges just like this kind of six style imp. So when we talk about cladrabine and fluorabine, what happens with these puppies? Fluterabine. Oh, you just made it guys. These get brought into the cell and then what happens is they act like nucleioide analoges. They're basically a nitrogenous base with a ribbo sugar. They don't have a phosphate. they get into the body, they get phosphorolated and they turn into kind of a deoxy ribboucleotide, but they are not a true nucleotide. They're a mimic. And usually for these, it's going to look like um like an ATP mimic. So it's going to look like an addinine triphosphate mimic. All right? Usually this is going to be 58:08 something like for example, this is era ATP and this one can also make kind of an ATP mimic as well. Basically, they're going to act like a nucleotide. DNA polymers will be none the wiser. It's going to run down. It's going to say, "Okay, there's a red one. I'm going to do a blue one. There's a red one. I'm going to do a blue one. There's a blue one. I'm going to do a red one. There's another blue one. I'm going to do a red one. And then it's going to get to this red one. It's going to say, "Oh, I need a nucleotide." And then it's going to grab this ATP mimic. When it grabs the ATP mimic, it'll bind it on. But guess what? There's no point where you can connect the nucleotide on. And so what happens in the same way? We terminate DNA elongation. That's the concept here. And also these in high amounts, what can they do? they act on another like sub another receptor site or a site on the DNA polymerase bind on to it change its shape and so now it can't actually do its function so it can also inhibit DNA polymerases right so that's the concept here is that these are all going to get incorporated here and what are they going to do they're going to uh same 59:07 thing inhibit DNA elongation they're going to terminate that process all right wow Now with all of this being said, there's one more thing I want to add up here. All right. The reason why I say that is when we talk about these, we see these mechanisms, these three primary mechanisms. There's one more thing that I want to discuss. When we talk about purines and we want to turn it into a ribboucleotle, right? All we're doing is we're adding on a sugar and a phosphate group. But then when I want to take this ribboucleotide and turn it into a deoxy one, so I can actually incorporate, I can't incorporate this into DNA. can only incorporate this into DNA. I need an enzyme. And this enzyme is going to work right here. And this enzyme is called, and I'm going to abbreviate it for right now, but it's called ribo nucleotide reductase. All right? So, we need to have drugs. We have we actually have drugs called ribo nucleotide reductase 1:00:09 inhibitors. We don't talk about these much because it's primarily like if we had a pure drug that does this. It's only truly one. It's really only one drug that truly comes in here and actually inhibits this enzyme. And if I inhibit this enzyme, can I turn this from a ribo or an oxy to a deoxyucleotide? No. And so I decrease my number of deoxyucleides. I decrease the DNA process. Tell me that's not cool, right? So what would this drug primarily be? Well, I told you Jim cytoine has ribboucleide reductase activity at high concentrations, but it's not a pure RNR inhibitor. The primary one is called hydroxy ura. And we talk about this in things like cickle cell. We talk about this in milo proliferative neoplasia. That's where it really comes into play because it's actually going to help to decrease the doxy ribboucleide processes, decrease the DNA formation in these rapidly proliferating uh stem cells inside the body. All right, we hit pretty good on the anti metabolites. Let's now move on to the next case here which is okay we got to keep going down 1:01:09 the line we get the S-phase inhibitors let's move into the next part here we did anti metabolites let's talk about topoisomease inhibitors all right so now we're going to move on to the next category which is our topoase inhibitors so again it's kind of like in the general discussion of what topo isomeases do we talked about this a lot in the DNA replication video but if you guys remember let's say that here we have our replication bubble right and then we create something called the replication fork because you know there's going to be that enzyme hilicase which is just going to be barreling through unwinding the DNA and creating this little replication fork and this area where it's kind of all occurring is called the replication bubble. Well, what happens is whenever hilicase is kind of unwinding proximal to that it gets really really tight. the DNA gets super coils and so you have these enzymes called topoisomeases right so this one right here is going to be topo isomease and we're going to talk about this one type one right this one over here we'll talk about in a second is going to be topo 2 what happens is topo 1:02:11 isomease one let's just say we kind of show this with two little arms one arm is going to make a cut all right so basically let's say here's all this like really really tightly wound up DNA. Imagine this. If this guy is trying to unwind the DNA and it hits into this area where it's like super densely coiled, is it going to be able to keep unwinding? No. It's going to hit like a road block. So what we want to do is we want to unwind the DNA just a little bit to reduce the super coil so helicase can continue at that replication fork. So does has one arm that makes a cut, lets it unwind. After it unwinds, then it takes its other arm and says, "Okay, we unwind it pretty good. We got rid of the super coil. Boom. Let's click that strand back together." And that's what it does. And it has that other arm which is going to relocate them. You can kind of think about it like this. Here's the super coiled DNA. Here's your super coil. All right? The super coiled, let's say super coiled DNA. Then the top 1:03:11 isomer is going to come in here. What's it going to do? It's going to make a cut, right? And so when it makes that cut, it introduces this little cut right here. Right? There's the cut. Then what it does is when it allows that cut to take place, it allows this thing to kind of uncoil a little bit. So it allows for it to unwind. So that's what's going to happen is we're going to allow for unwinding of DNA and that's going to help to alleviate some of these super coils. Here's the next thing is then what we want to do is is I'll represent this in a different color here. We'll do blue. Once we've you see how it's really really tightly packed here and it's less tightly packed here. Then what we'll do is we'll bring these together. We'll reigate them together. Right? So then we'll have reloation of unwinded DNA. When we give topoism race inhibitors, what we want to do is is we want to 1:04:12 allow for that arm to cut to go ahead. But when we want to glue it back together, we want to block that one. So when I give a drug like a topoase one inhibitor, there's a couple different drugs. Now I remember the one it looks like an I. The only I remember the different types of drug categories is irreot. So it looks like a one. So I taken and topotin. These two drugs are going to be topo isomerase one inhibitors. What they're going to do is is they're going to come over here and they're going to inhibit this enzyme. If I inhibit this enzyme, what will happen is I'll allow for the super coiled DNA to make a nick. So this is going to occur and I'm going to let it unwind. What I'm going to do is whenever it comes time to relyating it, I'm going to inhibit that step. Now, this will stay broken. So, it's going to cause this single stranded DNA break. And we'll kind of represent this as like a little jaggedy edge here and a little 1:05:13 jaggedy edge here. We're going to cause single strand DNA breaks. And we're not going to reloate them. So, here's going to be a single strand DNA break right here. And then what we're going to do is is we're not going to allow for the relocation to occur. So then if you think about that what that'll do is is that'll allow for this thing to crazy unwind and also it'll still create torsional stress proximal to that replication fork. So helilicase still won't be able to do this and on top of that this DNA is going to unwind so significantly you're not going to allow for DNA replication. So that's what I want you guys to think about. Super coil DNA we will make the cut. So there'll be a cut single strand DNA cut and unwinding of the DNA. What we will then not allow for this this enzyme to do then is to relogate it. It'll stay broken, unwind and DNA replication won't 1:06:14 be able to occur. That should make sense. Topo isomease 2, it's a similar thing. It's going to inhibit topo isomease 2. Now, one is it causes one single strand to break. Here's your super coil DNA, right? What's it going to do? It's going to boom. It's going to break break both strands. So, it's going to cut double stranded DNA and it's going to allow unwinding of the the DNA, the super coil DNA. All right? Unwinding of DNA. So, we're going to make the cut. Then we're going to allow for this thing to uncoil. But then when it comes back to relyating it, are we going to allow for that releigation to occur between the two double stranded DNA strains? No. And so that's what we're going to prevent is we're going to not allow for the releation 1:07:16 of the unwinded DNA. All right? So what's going to happen is when we give these drugs topoism two inhibitors what are they going to be this is etoposide and tenipocide these drugs are going to work to inhibit again the topo isomerase inhibitor and again it's got the two arms it's got the liase domain where it's going to cut and then it's also got the the li the actual liating domain where it's going to rely them together this is going to again inhibit that relyating domain And so this thing will cut the actual double stranded DNA. And I remember that one is it makes a single or one strand break. Two, it makes a two strand break or it breaks both strands of the DNA. The only thing that's going to be different here is what's going to happen. Here's my double stranded DNA break. Am I going to rely this puppy on these 1:08:17 jaggedy edges? No. And if I don't allow for that process to occur, I'm going to again allow for the DNA to unwind. And not only that, but then I'm going to continue to have all of this torsional stress proximal to where the helilicase is working on the replication fork. So it's going to hit a roadblock and all of the DNA downstream is going to unwind unwind and you're not going to allow for proper DNA replication. That's the key here. Okay, so that's our topo isomease inhibitors. So, so far we take our nucleotides, our nitrogenous bases, we make nucleotides. Nucleotides get incorporated into the DNA. Anti- metabolites are inhibiting the nucleotides forming DNA. This we already have DNA forming and we're trying to replicate it, but we're going to prevent that from continuing by targeting the actual enzymes that regulate super coils. All right, the next step. So, this is again going to be the topo race numbers. Now we're going to come down and talk about microtubial inhibitors. 1:09:20 Microtubial inhibitors can be broken down into two categories. So depol I'm sorry polymerization inhibitors and depolymerization inhibitors. So your polymerization inhibitors I like to remember the vinka the vinka alkyoids. All right. So the vinka alkaloids and there is two categories here or two drugs that I want you to remember and it starts with a V. So it's vincine and vinlastine. So venristine and vinlastine. All right. What happens is these drugs are really cool. So you have these different types of tubulants. So you have what's called alpha tubulin and then you have what's called beta tubulin. And then when these two combine they make heterodimer and these heterodimer is going to be your tubulant dimer. So we'll have what's called a tubulant. It's a heterotubulant dimer. And then if 1:10:20 you take a bunch of these dimers guess what? And you combine them together you will make your microtubial. Right? This is how you make your microtubial. Now microtubules are an extremely important component of allowing for connection between what? Between the centrosome which is kind of like this like area here towards the end where the motic spindle begins to formed. This is going to send these microtubules out from the in poles here. So here what we're going to do is we're going to have this centrosome here. Centrosome here towards the other end. What we want to do is is we want to be able to start sending these little pieces out. We want to send out these motic spindles which are pretty much primarily microtubules. In order for me to do that, to allow for that process to occur, I have to cause these things to be formed. I have to polymerize them. So, I need to go from here to here to here. And then I need to allow for this one to go from here to here. This one from here to here. Here 1:11:21 to here. Right? So I start off with the formation of the spindles, right? Of the spindle spindles. And then from here, if we move down, look what happened. We kind of just started to kind of inch them out. Then what we're going to do is we're going to go to this next stage. And at this stage, this is what we call metaphase. This is basically whenever the microtubules meet the chromosome at the kicore, right? Right at that centromeir there's a little protein called the kitoore. We're connecting those microtubules at that portion there at that centromeir where the kicore protein is. Then what we do is is in order to separate. So here's the chromosome at the centromeir we can split these into sister chromatids. But in order to do that I need to break the microtubules down. I need to depolymerize them because they were really long connecting all the way to the equatorial plate. Then what I need to do is I need to shorten them to bring this sister chromatid which way? I want to move this one this way, this one this way, this 1:12:23 one this way, this one this way. So I need to depolymerize them, right? And this is going to be the anaphase. So polymerization of microtubules really influences metaphase. So if I give a drug like these the vinka alkaloids what they do is they come over here and they bind to the betatubulin when they bind to the betatubulin basically they inhibit the formation of dr and when you inhibit the dimer formation you get less of these and then you inhibit the formation of microtubules. So you inhibit the polymerization. So at which point are you going to inhibit? You're not going to allow for this metaphase portion. So this gets shut down. I can't bring these out and connect to the actual chromosomes. And therefore, if I can't connect to them, would I even be able to proceed to anaphase and separating the chromatids into each cell? So would I be able to take one cell and prevent it from forming two cells? Yes. Do you see how this is an Mphase inhibitor, but it's 1:13:25 particularly at the metaphase portion? So we've talked about drugs like the anti metabolites, how they work in the Sphase. We talked about the topo isomerase inhibitors. How they inhibit DNA replication by working at the super coils. Topo one is S-phase. Topo 2 is G2phase. Which ones are these doing? This is working in mitosis particularly at metaphase. Compare over here. Now if you compare over here, now we're going to go the opposite process. So depolymerase inhibitor depolymerization inhibitors are called taxes. So these are your taxes. And this is going to be two drugs. uh we're going to have what's called dosaataxel. So we have what's called dositaxel and pletaxel. And we're going to start off with what? We're going to start off with a microtubial. And then basically we're going to go the opposite direction. We want to take the microtubial and we want to break it down into our dimer. So we're going to break it down into our tubulant heterodimer. 1:14:26 So this is going to be our tubulant dimer. And then we want to break these down into your alpha tubulant and your beta tubulant because what we want to do is we want to start breaking these microtubules down into their small components so that we can start moving what? So think about this here. We start off we have the motic spindle beginning to form. Then they move and they connect to the chromosome at the the centromeir via the protein the kaore. Then and this is via the polymerization. Then we need depolymerization to start breaking down the microtubules and shortening them so that they can move in which direction? They can move towards this pole and this pole because I want to eventually have two cells with the same amount of genetic material. So this portion here which I want them to depolymerize, right? This is where I'm inhibiting it. Right? So we start off with the motic spindle is beginning. Right? So mitoic spindle is forming here. 1:15:28 Then we have our metaphase kind of like right here where they're connecting along the equatorial plate. And then we have anaphase. At which point is depolymerization super critical if we think about this pretty straightforward. Well, it's not this one. It's really primarily this state. And so what we're going to do is is we're going to inhibit right here. We're not going to be able to separate the sister chromatids and therefore you're not going to get enough genetic material into the appropriate daughter cells. So this is what I want you guys to remember is we're inhibiting the depolymerization. So you're getting less tubulant DR, you're getting less of these alpha tubulants, less of these beta tubulants, and you're getting these uh microtubules to stay in their stabilized state. They're staying in the stabilized state and they're not breaking down. All right. So so far we've talked about S-phase inhibitors with anti metabolites. We talked about the um G2phase inhibitors which is going to be particularly the topic 2. We talked about the Mphase inhibitors which 1:16:29 is going to be your microtubial inhibitors. Let's talk now about some of those cell cycle non-specific ones. The ones that are going to be able to inhibit any phase. It's not a specific phase. They could do G0, G1, G2, Sphase. It doesn't matter. They can even they could do the G0ero phase if they wanted to. These are going to be your alkalating agents and your anti-tumor antibiotics. Let's move on to those. Anti-tumor antibiotics are actually really interesting and they're extremely potent, especially the cell cycle non-specific ones. The cell cycle specific is your bleomy and again this is like a you know a broken record but it's really going to be specific in which phase. So it's the G2 phase. You know all the other ones that we're going to talk about here they're going to be more particular towards um again non-specific. So it can occur at any state. When we talk about bleomy what's really interesting about bleomy is let's say here's bleomy. It can have I'd say an interesting kind of thing. He can have a DNA binding domain, right? So here's like a little portion where it could bind to the DNA, right? So let's 1:17:29 say here we have a portion called the DNA binding domain. And let's say here it clicks in to the DNA, right? So it's binding onto the DNA. So it has a DNA binding domain. DNA binding domain. All that means is it's the portion that binds with the DNA, right? The other portion is kind of where it's a little bit more critical. The other portion is like right here. This is an iron binding site. All right. So, right here is a metal binding site. But primarily this is an iron binding site. And what happens here is whenever it binds to the DNA, the bleomy, right? Iron can kind of stick into this pocket. when it binds into this pocket, it creates a I I'd say like a a complex that can generate reactive oxygen species. So essentially, it could take something like oxygen that may be nearby and convert it into different types of free radicals, right? So you can 1:18:30 generate a lot of reactive oxygen species essentially. So this is going to bind with the DNA, helps to bind iron. Iron is going to convert this into different types of super oxide annions. Maybe you make hydroxide ann ions, right? So you'll make the hydroxide ones as well, right? And these are going to lead to high amounts of these reactive oxygen species. Reactive oxygen species are extremely dangerous to proteins, lipids, and DNA. And guess what this is going to go and do? It's going to go act on the DNA and lead to damage to the DNA. And when I start damaging the DNA, guess what? If I don't have those repair genes that are coming in and fixing this, guess what's going to happen? This cell will not be able to go through the replication process. So, it'll produce DNA damage. And the key thing is is if this does not go through the actual repair process. So, if our DNA repair enzymes aren't able to get in there and fix this during that G2 phase, what's going to happen? 1:19:31 It'll proceed to go into dying. It actually will undergo death. So, that's why this is extremely important. So bloomycin very very powerful uh type of drug works in the G2 phase has a DNA binding domain where it binds onto the DNA has an iron binding site where it binds into this little pocket then it can create a complex which generates reactive oxygen species produces DNA damage if your DNA repair enzymes don't fix this this will die this cell will die all right similar concept now we have the cell cycle non-specific agents so this is going to be things like docor rubicon And there's another one called donor rubicon. So donor rubicon and then there is another one I'll briefly talk about this one called dactenomy. Now what I want to do is dctenomy really it only does one of the three functions that doc rubison and donor rubeson do. I want to put a little asterisk next to this because this thing 1:20:31 has three different functions. So, what I'm going to do is I'm going to talk about the three different functions it has and then I'll tell you which one of those three only this one has. All right, let's say here's the drug, right? It obviously has a DNA binding domain, right? That's one thing. So, one of the things it can actually do here is it has a DNA binding domain. So, that's really really important. So, it allows for it to be able to bind to the DNA, right? So, it can stick to the DNA. The other thing is it has a iron binding site. Same thing. So it has an iron binding site. And so because of this, it has a couple different types of things that it can do. You probably be like, "Oh, it's the same thing like bleomy." Not necessarily. It can do a couple different things. Because it has a DNA binding domain. it can bind in areas near another enzyme called topoisomease 2. And so what this 1:21:32 has the ability to do is is it has the ability to inhibit inhibit a very beautiful enzyme that we talked about already. So if you remember that enzyme's function, you'll remember this is one of the three functions of docar rubin and donor rubicon. This is your topo 2 uh enzyme and so it's going to inhibit the topo 2 enzyme. Can you guys remember if we have this drug bind onto the DNA inhibit the top 2 enzyme what's that going to do? it's going to produce come on double strand DNA breaks that don't get relocated and so essentially you end up with increasing doublest stranded DNA breaks and this leads to unwinding of DNA and basically you can't allow for that replication fork to continue and so this is going to lead to decreased DNA replic replication. So this is going to decrease the DNA replication process at 1:22:32 that replication fork, right? It's going to cause all that torsional stress. All right, that's one of its three functions. I think you can guess the next one. If it can bind to the DNA and it has this little iron binding site, well then guess who can bind in there? Iron. And if you combine iron, what can it do? It can take oxygen and turn this into like a super oxide annion. It can make hydroxal annions. And these are called reactive oxygen species. And these will produce DNA breaks. And if you produce DNA breaks and you don't allow for that actual fixing, you don't allow for those DNA repair enzymes to come in and actually fix this process, then what happens? Then the actual cell will die. So that is really the key thing here is that we're going to generate lots of reaction 1:23:33 reactive oxygen species, lots of DNA breaks, and that is definitely going to hinder DNA replication because if you can't fix it, the cell will die. One other one, doc rubison, donor rubeson, and dactenomy are kind of like they're kind of cool in the sense that they can really because they have a DNA binding domain, they can actually interact with certain nitrogenous bases and basically they can kind of act like um like a little a you know a person to block between the two. So if I have a nitrogenous base over here, a nitrogenous base over here, and I have this drug in between, it can intercolate. It's called intercolation between the actual DNA strands. Now imagine if I have this intercolating these, can DNA polymerase get in here and read this? No. So what happens is whenever DNA polymerase is trying to go down and read this DNA strands and create a new strand, it runs into this big beast. And guess what? He says, "I ain't moving." and we inhibit this 1:24:34 process. And so that that is really key is so we can have something called intercolation. So intercolation of DNA and this inhibits DNA polymerase. So again what happens here is this gets in and binds in between the nitro and this is not a coalent bond. It's a non-coovvealent bond. That's what alkalating agents do. Not this one. It just goes in and kind of creates a non-coovvealent bond, intercolates in between the DNA, blocks DNA polymerase from reading these strands and making new ones. So, it's going to inhibit DNA polymerase. And if you inhibit DNA polymerase, can you replicate the DNA? No. And if you can't replicate that DNA, you ain't going to make no new cells. And that's good with cancer, right? So, that's the three mechanisms. Three mechanisms. One is it inhibits the topo isomease 2 enzyme. Second thing is it increases reactive oxygen species. Third is it intercolates 1:25:39 the DNA. Dcttoy only does the third action. That's all I want you to remember. I'll write that down just so that you guys know that this has three. Dcttoy really only does intercolation. So it really only performs intercolation of DNA whereas docar rubicon and donor rubiconin this one it can do it all it can do all three so that's what I want you guys to remember so so far with anti-tumor antibiotics we have cell cycle specific blem G2 phase only does reactive oxygen species cell cycle non-specific doc rubisin donor rubisonin three types of mechanisms reactive oxygen species inhibits topo isomease 2 which we already talked about and it kind of acts like a little blocking person a security guard between the night the nucleotides you then don't allow for DNA polymerase it hits a roadblock it can't continue if you have this big boofy thing blocking its way dctenomy only does that little big 1:26:39 boofing thing where it blocks the way that's what I want you guys to remember here all right so let's move on to alkalating agents alkalating agents are cell cycle non-specific agents meaning that they don't affect any specific phase you know they don't really have to work only in G1 or S-phase or Mphase anything like that. So they can work at any phase including the G n phase. So the thing about that is when we talk about these drugs we can break them into three different categories. One is your nitrogen mustards, right? It's not the same mustard you put in your gizzies at a as at a baseball game. But there's a couple different drugs here. One is called cylo phosphomide. Another one is called I phosphomide. And then the last one here for the nitrogen mustards, you know, we don't use this one often, but you can use it in multiple myoma, and that's called melphan. It's usually as a conditioning agent sometimes. Uh, triazines. These are basically they're all going to form generally some type of covealent bond, especially these. This one right here is going to form some type of methylation group. And this is usually going to be what's called teozolide. 1:27:43 And then lastly is you have your platinum compounds. Platinum compounds basically they can generate coalent bonds between again the different components of the DNA strands whether it be inter or intra and we'll explain what that means in a second but they utilize an a metal ion that these nitrogen mustards don't thus the name platinum and so this is going to be things like cis platin carbo platin and then you also have oxaloplatin. Now, with all of this being said, how do they work? We're not going to complicate this. It's not complicated. When you give these drugs, the nitrogen mustards, all they really do is they're basically going to be, think about it, it's like um it's like a piece of gum. Here's this like this molecule. And this piece of gum is going to kind of form in between the DNA strands. Now it can do this in a way where you could actually generate bonds maybe between this nucleotide and 1:28:44 this nucleotide that's called a intrand cross link or you could form covealent bonds between this nucleotide and this nucleotide that's called interstrand cross links and so you can get different types of cross links right all I want you to know is that you going to make a lot of cross links between the DNA if I make cross links between the DNA and these are covealent bonds on. So let's call these cross links. And then let's annotate something here. This is again what kind of bond? We'll just represent this in green over here. These are going to be very powerful types of bonds, strong bonds. This is a covealent bond. All right. So this is a covealent bond. The ones up here that we talked about which are again a part of your anti-tumor antibiotics, doc rubison, donor rubicon, dctinomy, those intercolate but they don't they form weak bonds. They don't form coalent bonds and again these crossings can be intrarand or interstrand. Think about how this works. The DNA is supposed to be sandwiched together, right? So these 1:29:44 are generally they're forming hydrogen bonds between this nucleotide and this nucleotide, right? So they should be very very close. This guy comes in and sandwiches between them and says I'm going to hold you together. And now if it holds it together when I want to take and separate, right? I want to take and I want to separate these out. And we use different types of proteins to do that, right? What are the for example what are the different types of protein that separates the actual DNA strands? It's called the DNA a protein. What helps it to keep it apart? Single strand of binding proteins. What's the enzyme that comes through and opens up the replication fork? Hilicase. What's the enzyme that runs through and reads the DNA makes new DNA? DNA polymerase. Can you do any of that? No. So all of these enzymes that you need to perform these functions, for example, things like DNA polymerase, right? Here's one. He's supposed to get in there. Your DNA pull. He's supposed to get in there and read the DNA. Helilicase is supposed to get in there and it's supposed to separate the actual DNA strands at the replication fork. Can he do that? No. It's literally it's like 1:30:44 gluing the strands together. And then there's other ones, right? So you have DNA a proteins. I like to do it like this because it kind of looks like it hooks the DNA and separates it. And you also have other ones called singlestranded binding proteins. Either way, all of these puppies are supposed to literally be utilized to get into the DNA, read it, and make new DNA. Are you going to allow for that process to occur? Are you going to allow for that separation and reading? No. All of that's inhibited. And so what you do is you decrease essentially DNA replication because you can't separate the strands. It's the exact same down here with this one. So that's why it's kind of nice when we think about this because the only thing that's different, the only thing that's different, so let's actually we're going to take a little beat here. We're going to come over here for a second because it is exactly and I mean exactly the same. These are compounds. Uh actually let's let's do this the correct color. Come on, Zach. You're going to have this guy 1:31:44 coming down. But what's the difference? This is going to be a piece of chewing gum, let's just say. And it's going to have a specific ion called platinum in it. All right? And what's going to happen is this is going to go in here and this chewing gum is going to do the exact same dang thing. It's primarily more you see this being more intra strand but it can cause interstrand but either way this may be connecting these and these. This may be connecting these and these but either way the same concept exists. Can I have all of these enzymes get in there and separate the DNA and read it? Can DNA polymerase get in there? No. Can hilicase get in there? No. Can our DNA proteins separate the strands? And can singlestranded binding proteins hold it apart? No. And if we can't do these particular functions, can I even allow 1:32:44 for DNA replication to take place? No. So, I'm going to increase my cross links, which decreases that DNA replication. That's the concept I want you to understand. Right? So, we're forming cross links and these cross links, they're not weak, man. They're pretty strong. And because of that, it makes it really hard to truly perform that replication process. And that's what I want you guys to consider here is that we are really doing it through that concept. Now, teemazol similar, but it's not completely the same. For example, when we talk about teemazol um and these triazines, what happens is this drug it gets converted into like a complex that primarily its job is to methylate. And so we call this component, it's called MTIC. Don't go too crazy memorizing all of that. What I want you to really just simply know is that what it does is it takes a methyl group and it adds it on to specific nucleotides. And when you add this methyl group on, what it may do 1:33:47 is it may allow for a mismatching. So maybe this one was supposed to go with this one. Now it mismatches it with the improper nucleotide. If you cause mismatch kinds of processes and you don't allow for that repair process to occur, that's when we start seeing issues because it actually does distort the DNA helix. That's where we start to see problems. And so because of this, you end up with what's called a mismatch. you end up causing mismatch nucleotides, right, through this kind of issue. And this again makes it really hard. It distorts the DNA double helix, but on top of that, it really makes it hard for all of these enzymes to perform the DNA replication process. And that's going to shut down that DNA replication. All right? So, you're going to increase your mismatch between those nucleotides, and you're going to shut down that DNA replication by methylating these. And that's going to be the issue with this drug. All right. So, so with alkalating 1:34:49 agents, again, we have these three categories. The biggest thing I need you to remember is they like to form cross links. The difference between these two is this has platinum involved. This one is it methylates structures to allow for that improper matching of nucleotides. All right. Now that we nailed this one and destroyed it, let's go into the next portion because we talked about all the drugs that influence the cell cycle. Now, let's look at this at a different way. Let's say okay we talked about the drugs such as the anti metabolites and how those influence pyne perimeitine synthesis and incorporating that into the DNA. We talked about topo isomease inhibitors and how they really act on the super coils and how they really kind of prevent the reloating when we have super coils. We talked about the microtubial inhibitors and how they basically inhibit them from polymerizing to connect at metaphase and how they inhibit them from depolymerizing to break apart during anaphase. We talked about drugs that basically can intercolate. In other words, they can get into the DNA and kind of just block it. They block DNA polymerase. They can generate free radicals. And then in some 1:35:51 ways, they can even do Dr. Rubin and Donna Rubeson generate some topo isomease 2 activity. And then lastly, we talked about the drugs who can generate a cross-linkage of nucleotides with a strong bond making it hard to separate the DNA, generate a replication bubble, fork, and then replicate the DNA in general. Now that we've done that, let's move on to what about drugs that can target upstream pathways that influence the cell cycle because it all leads to that CDK4 and six. What about all those different pathways that influence CDK? CDK itself do we have drugs for? Let's talk about that. All right, so now we're going to talk about our protein kynise inhibitors. So, you know, there's there's a lot of different proteins that are basically regulating your cycl dependent kinases, right? because that's that's really what we kind of talked about that really kind of pushes the cell list. Hey, let's go through because it's at that G1S checkpoint and we really want to have something that says, "All right, you're good. Go ahead and proceed." And if we have something that's constantly stimulating that like a like a nat at a barbecue, then it's just going to keep continuing to go 1:36:50 through that cell proliferation process. And so it's again, it's kind of reminding ourselves that we have that CDK4 and six enzyme. And again, do you guys remember what it does? Well, it does what? it adds the phosphate groups onto our good old friend here, the retinino blasto protein, right? And it's holding on to the E2F very tightly. And so when it adds the phosphate groups onto that, what does it do? It then releases E2F. And if we release E2F, that E2F is a very powerful transcription factor that is capable of doing what? Well, it's capable of getting in here activating on specific protoonco genes. And if it acts on those protoonco genes, it's going to stimulate very specific genes that are going to enhance what type of process the initiation of going from that G1 into the Sphase. And so if I want to stimulate this process and allow for that cell to go through the proliferative phases, guess what? That's what this is going to do. And it's going to really push this to occur. And that's going to allow for the cell proliferation. So what I want to do is I 1:37:51 have to remember that there's all of these pathways coming downstream that are influencing this. Right? So for example, here is this molecule. What did we say this one was called? This is called BCR aable. This is a constitu um it's basically a non-membranous tyrroscen kinus. It's in the cytoplasm and it can be activated for multiple different reasons. But one of the cool things about this is that it really helps to drive some of the similar pathways that a lot of these receptors do. We also have EGFR receptors. When EGFR is activated by a growth factor, it triggers intracellular pathways. Whenever the tyrroscen kinases that are associated with alk are activated by specific growth factors, it triggers an intracellular pathway. Whenever the jais kynise receptors are activated by growth factors, it triggers an intracellular pathway. What are those pathways you ask? It can all lead to an increase in PI3K AKT signaling which leads to the mTor activation. It can also increase the the activity of RAZ which is a GDPAS which then leads to 1:38:53 the activity of increased RAPH which then leads to the increased activity of mech and this is all a part of our map kynise pathway. And then we can also activate signal transducers activators of transcription and so all of these to a degree have the capability of increasing these pathways. the Jack stat pathway that's primarily only going to increase stat but all these other ones can influence it pretty much the same way and so these are generally trying to increase the activity of these specific pathways this goes up this goes up and what happens is what do these do these lead to a downstream effect on cycl dependent kinases and if you activate the cycl dependent kinases what will it do it'll trigger this process right so that's all of this upstream to downstream effect. Now, think about this. All right, think about this. If I give drugs that can act on these different levels, I could potentially shut down these pathways. So, let's say 1:39:54 I give a drug that inhibits the BCRA tyrroscen kinases. What would that drug be? This is usually any of the tyrroscen kynise inhibitors, TKIS, which you'll see here, usually end in I nib I in IB. So, this one is example a mat to nib. If you can't remember that, that's okay as long as you see the inib the eGFR, right? And so, well, actually, before we do that, this is inhibiting this guy. It's going to basically bind to this ATP binding site. So, it'll bind to the ATP binding site and that will inhibit this enzyme and that'll shut down that pathway. And if we shut down this pathway, we're going to drop all of these levels and that's no longer going to stimulate CDK4 and 6. It's going to inhibit it. That'll shut down the phosphorilation of retininoblasto. That'll shut down the release of E2F. If I don't have E2F, can I stimulate transcript? Can this transcription factor stimulate specific protoonco genes? No. It's going to inhibit them. And instead, we will put the brakes on 1:40:54 the checkpoint and say, uh-uh, don't go through any more cell proliferation. Tell me that's not a cool mechanism. Right? We use this a lot in CML, believe it or not. EGFR TKIS. If I give this drug, right? What it's going to do is it's going to act on the tyrroscen kynise portion of this receptor and that's going to do what? Think about it. It's going to inhibit them. If you inhibit them, you shut down this pathway. And you do this. It's the same thing. It's the same thing, right? Al tyrroscen kinus inhibitors. We're going to inhibit the tyrroscen kynise of this receptor. If we do that, we shut down this receptor signaling and we shut down this. If we give a drug like a jack stat inhibitor, it's going to act on the Jonis kynise portion of this receptor and then do what? Shut it down and that's going to decrease this pathway. So then what are these drugs that we can talk about? Well, this is a TKI and this is a TKI. So it's going to end in IB. It's just they have a beginning 1:41:55 different kind of prefix asa merinib. All right. So there is the ionibanib this is going to be electinib electinib see the inib IB and then there's the jack stat inhibitors and this is going to be rox lit nib and you'll see the inibb all right now you can kind of see a pattern here and that's pretty cool when you see these protein kynise inhibitors the small molecule inhibitors now The other concept is you see this pathway the RAZ raph mech which are part of that map kynise pathway we actually you have drugs that can inhibit the pi3k and the AKT and even the mtor pathway we're not going to be seeing that too much as for with respect to things for step one step two but you will potentially see some drugs that are involved in the map kynise which they're basically raph inhibitors um and so let's say that I have some drugs here that are going to have the possibility 1:42:56 of um let's kind of do it like this they have the capability of inhibiting these pathways and if that happens they shut down this kind of downstream effect. What could be some drugs here? Well, there's one particular one and it works on the raph but we call this aph inhibitor and that graph inhibitor that we really are speaking of is called vimu rafafhanib. There is other ones like mech inhibitors but we're not going to talk about that but graph inhibitors are called vimu rafafa nib and I like to actually remember this one with raph raph all right so that helps you a little bit to remember that that's kind of a raph inhibitor which is a part of the map kynise pathway all right the last one is we talked about all the upstream ones kind of leading to this kind of inhibition of CDK4 and six if we're using these drugs that are inhibiting that what What if I have a drug that can go straight directly to CDK4 and 6? That'd be a CDK46 inhibitor. 1:43:59 If I could inhibit that, that would be the same kind of effect and it would be very very potent. We do use this drug. It's very, very commonly utilized in breast cancer. Usually in combination with other things like tmoxifen or usually things with like aromatase inhibitors, but this is a pretty good one in metastatic breast cancer. All right? Especially if they're um usually estrogen receptor, progesterone receptor positive. But this right here would be palpo cichlib. This is an example one. So again, usually you're looking for the cichlib portion for the cdk46 inhibitors. All right. So this is what I want you guys to remember when we talk about your protein kinase inhibitors. Usually if they're TKIs, they end in. And then if it's a bra inhibitor, remember raph and vimu rafafhanib. And then cichlib is your cdk for six inhibitors. Again, you're inhibiting the upstream pathways, mid-stream pathway, or the cycl dependent kinases, but either way, you're inhibiting the protein kinases that regulate the cell cycle, and you 1:45:00 can then shut down that checkpoint where they don't continue to go through cellular proliferation. That's cool. What if I use drugs to inhibit this same pathway from this point, but it's nothing to do with the receptors or intracellular pathways here. It has to do with blocking hormones. Would you believe me? That's okay if you don't. We're going to show you. So, hormonal therapy is commonly utilized in cancers like prostate cancers. It's used a lot in breast cancer, heavily in breast cancer, especially if they're estrogen receptor, progesterone receptor positive. We utilize these. So, you got to go back to kind of a little bit of the hypothalamic pituitary gonatal axis. Your hypothalamus makes something called GNR. that tells the anterior pituitary to make something called FSH and also another molecule called LH. Right? So, hypothalamus makes G&R. G&R tells the anterior pituitary to make FSH and LH. FSH acts on the ovaries and LH acts on the light cells of the testes. And this 1:46:02 pumps out a hormone. This pumps out a hormone. The hormone that's made from the presence of these is going to be testosterone from the testes, right, from the nudes. And then that testosterone can actually be converted into something called DHT. And that's really what is the driver of patients who have prostate cancer. And so we want to be able to shut that down, right? For females, when it acts on the ovaries, it triggers them to produce something called estrogen. And so if a patient is unfortunately producing let's say large amounts of estrogen or large amounts of testosterone that can lead to some particular issues here right testosterone can actually eventually again it gets converted into what's called DHT if you really want to you know we call this one there's an enzyme called five alpha reductase and that eventually converts this into what's called DHT if we really wanted to remember and this is an androgen so it can bind on to different types of andigen receptors essentially but estrogen let's think about this one for a second. Estrogen, 1:47:03 you know what it does? Estrogen can then go over here. It can actually cross the cell membrane because it's it's it's lipid soluble. It's a steroid. And when it does that, it binds on to these different estrogen receptors that are present inside the cell. When you bind on to these estrogen receptors, you activate these and these then lead to the stimulation of our good old friends CDK4 and six. And what does this do? Adds phosphate groups onto who's this friend retinol blastoma. Who's it holding on to? E2F. If this gets phosphorolated, what does it do to the E2F? Spits the E2F out. If E2F is spit out and it's free, right? What does E2F do? It says, "All right, let me act on these particular genes." And then it acts on these specific protoonco genes, stimulates them, which then does what? drives the person to go from the G1 phase, right? So, it's going to stimulate some 1:48:03 specific type of protoonco gene which then stimulates to go from that G1 phase to the Sphase, which is just going to push the cell to keep going through that replicative cycle. All right, that's really interesting when we think about that. The other concept here is that not only is estrogen made from the um ovaries, all right, but you also have testosterone can get converted into DHT, right? There's another thing here where we can take something like an androgen and convert it into estrogen which is kind of interesting. So you know in uh females as they get older um their atapost tissue tends to kind of increase and so what happens is why postmenopausal women are high risk for breast cancer um they can increase the production of estrogen I'm sorry uh androgens androgens. So your atapost tissue will produce some things like androgens and so does your adrenal uh gland. So your adrenal cortex can also make androgens. Now why is this relevant? Well, when you make androgens, there's an enzyme here and this enzyme is called aromatase. So it's called aroma 1:49:06 tase. And what happens is aromatase essentially takes these androgens and spits them out and converts them into estrogens. And so if you make if you have a person who has a high risk of breast cancer, right, their atapost tissue, if they're obese, they may be producing a lot of androgens. A lot of these androgens if acted on by aromatase produces lots of estrogen. This acts in that breast tissue and increases the risk of developing things like proliferative tissue within those mammary glands causing breast cancer. So that's what we see there. The other thing here is that androgens also on their own again things like DHT or other androgens have the capability of binding onto these androgen receptors, right? And so if they bind onto the androgen receptors, they act just as though estrogen would, which was to do what? If they're stimulated, they're going to act on the CDK4 and six. And they're going to stimulate this puppy. And if we stimulate this puppy, right, he's going to release the E2F. And if we release the E2F, it's going to 1:50:06 drive this cell proliferation cycle. So what if I could come up with ways to shut down this pathway and shut down that that cycle independent kynise pathway? I may be able to shut down that cell cycle from continuing to go go. So let's do that. I'm going to give a drug which we use a lot in prostate cancer called Lupralide. And this is a G. So Luprolide is a G&RH agonist. It's a little funky the mechanism, but it's also kind of cool how they think about this stuff. So, what it does is, let's say for a second here, just follow me for a second. Initially, what it'll do is it'll help to kind of essentially stimulate the same pathway. It's going to act like G&R. So, what it'll do is it'll kind of create an environment of where you have high G&R. If you do that, you increase FSH, you increase LH, and that increase estrogen testosterone. You're like, "Zack, that doesn't make any sense." Hold on. When testosterone and estrogen levels go up, what that does is high testosterone and high estrogen create a negative feedback. So high 1:51:09 test, high estrogen, basically what that does is it creates a negative feedback mechanism. And when you create this negative feedback mechanism, it essentially shuts down the G&R pathway because it's like a protective thing. It says, "Oh, you better go down. Oh, you better go down. Oh, you better go down. And then guess what happens to the estrogen levels? They go down. What happens to the testosterone levels? They go down. What happens to the DHT levels? They go down. So that improves things in prostate cancer, right? And also lupide. I mean, you theoretically could drop this in patients who have maybe a need to drop those estrogen levels. Now, that's what I want you to think about is that G&RH agonists, they technically lead to, if you really want to think about it, they theoretically increase estrogen. They increase testosterone which creates a negative feedback mechanism to shut down that pathway. G&RH agonist they do this directly. They literally they directly lower the G&R effect. That drops the FSH that drops the LH that drops the estrogen that 1:52:09 drops the testosterone the DHT. This is a drug called degarelics. All right. Now let's keep going. What if I had a drug where it didn't affect any of the FSH? it didn't affect any of the LH. Estrogen got produced, but I wanted to block estrogen from binding onto the receptors. I could do that with ser. So ser basically are going to be able to come in and basically block estrogen from binding to this receptor. So when it does that, it shuts down this pathway. If it does that, it inhibits the CDK4 and 6 that then inhibits the phosphorilation that drops the free E2F levels that then does not activate the protoonco genes and that shuts down this pathway that's pretty cool, right? And so the drug categories here that we utilize often in ERP positive breast cancer is tmoxifen. 1:53:12 And there's another drug that we can use as a chemopreventive agent called Reloxifene. It's the same kind of drug category as well. All right, but that's what we would do there. Now, let's let's say that okay, we have another issue. We want to basically use the way of being able to block androgens from being converted into estrogen. I can do that with this enzyme and so uh or inhibiting that enzyme. And so I can use a drug to basically inhibit aromatase. If I inhibit aromatase, I basically don't convert androgens into estrogen. What happens to estrogen levels? They fall and then this pathway is inhibited. What would be some examples here? We use this, we use this a lot in again breast cancer. You can also use this um there's many other conditions, but I think the big thing to remember we'll talk about a lot in the indication section is going to be breast cancer, but this is going to be things like let anastriol like these are pretty common ones that we talk about there. All right? So they're going to inhibit that pathway. The last thing is what if I 1:54:12 wanted to block the androgens directly. I could do that. Especially in prostate cancer, I could block this directly. I could give a drug that basically comes here and says, "Hey, let me block these androgens from being able to bind to these receptors." And if I do that, I inhibit the CDK4 and 6, right? So that would inhibit this process, right? And that's going to still shut down this whole pathway. What's be some drugs that I could use here? This could be something like inzaludamide. Enza ludamide. So again when we talk about this we can see that you can have a lot of upstream pathways that influence CDK4 and CDK6. It could be things like protein kinases and you could have things like hormones that are influencing a lot of these. If we could target these hormones, target these protein kinases, we could potentially reduce the cell proliferative process and then treat these patients underlying cancers. Tell me that doesn't make sense and it's not cool. I hope that you guys understood this because now what we got to do is we 1:55:13 got to keep building. There's one more way that we can inhibit this. We can inhibit this another thing where we can again target receptors but we don't target the kynases. We don't target the hormones. We target the receptors by using monoconal antibodies. Let's talk about that next. All right. So let's talk about monoconal antibodies. So these ones are going to be very interesting. Usually anytime you hear monoconal antibbody or an immune checkpoint inhibitor you can think of the ending MAB right just like with the protein kynise inhibitors we talked about those for the most part like you know your TKIS we're ending in the inib you know your raphanib is we're going to be for your bra inhibitors and so that's going to be really important for monoconal antibodies immune checkpoint they usually end in map and you'll see that as we go through it but again it's the same concept man we're really just we're targeting upstream pathways and so you kind of just go back to this and it's going to become so redundant but you you just won't forget it. That CDK46 is really important here. And what is it doing? It's again phosphorilating which particular molecule? It's 1:56:13 phosphorilating the retinol blastoma protein who holds the E2F. If we add phosphates onto this, what does it do? It spits the E2F out. There's my green marker, my friends. So, if we spit the E2F out and it's free, we know that E2F is a transcription factor, a pretty powerful one at that. activates protoonco genes and if it activates the protoonco genes what will that do that will then stimulate the conversion or that kind of trigger if you will to go from the G1 phase and say all right you're good go ahead hut out hike go into the S-phase and begin the DNA replication process so it'll stimulate the particular protoonco genes and then drive them to go through that cell cycle right so we have a couple other pathways that are influencing this one you're probably dude this sounds familiar efr yeah but we're not targeting the tyrroscen kynise part of the receptor, we're actually targeting the receptor itself, the part that binds the lians. And so I can use a drug, it's called satuximab. So we use this a lot um 1:57:16 particularly in colarctal cancer. Um and so whenever we use this one, what it will do is is it will come and literally, I'm not kidding, it's going to be a monoconal antibbody. And so you have a couple different options here. Think about this. So we have here are the monoconal antibodies and here is going to be the growth factors and what your growth factors want to do the epidermal growth factors they want to be able to bind here. So what this monoconal antibbody will do is is it'll basically kind of essentially knock these out of the way. So we're going to push these little epidermal growth factors out of the way and these monoconal antibodies will bind. They'll literally bind to these receptors. And when you do that, you essentially kind of inhibit them. And if you inhibit this interaction now, you're going to do what? You're going to shut down the intracellular pathways. What are those pathways? I'm so glad you asked. The PI3K, AKT, the RAS, mech, the stat pathways. And so all of these will be shut down. You'll shut down that PI3K 1:58:19 AKT tour pathway. You'll shut down the RAZ, the RAPH, the mech, which is a part of the map kynise pathway, and then the stat pathway. And by doing that, what do you do? Well, you then say, if I don't have these all kind of activated, what's it going to do to the CDK4 and six? It's not going to stimulate this. Therefore, it will inhibit it. Are you going to phosphorolate retinoplasma? No. Are you going to release E2F? No. Your E2F levels drop. Can you actually activate protooncoins? No. Can you then put this cell into the proliferative stage? No. That is what I want you to know about this one. Another one is called a herto blocker. Her two blockers you want to think about something called tresusumab. Tresuzumab. This one is very very very important one in breast cancer. And what happens here again it's a monoconal antibbody. So basically you're going to have some type of lian that will bind to the heritu receptor. Usually these are some type of growth factor of some sort, right? And 1:59:19 you're going to have these monoconal antibodies. And these monoconal antibodies essentially are going to come and block that growth factor. And when it does that, it then says, "All right, cool. I'm going to shut this pathway down." And so now when I do that, I can't trigger these intracellular signals. And if I can't trigger these intracellular signals, can that I then lead to the activation of CDK4 and 6? No. And what do I do to this pathway? I shut that pathway down. So that's what I want you to remember. And then the big thing to take away from this is look at these kind of names. Mab mab that's a monocclonal antibbody. And so that's what I want you to think about. So we talked about drugs that target the tyrroscen kinases the inibs. It could be the bcrable one like the amatanib. It could be the egfr tyrroscen kynise like oamerinib. It could be the alc tyrroscen kynases like electinib. You have rxalidnib for the jackstat pathway. We talked about the ones that are inhibiting the raz pathway which is going to be the map kynise inhibitors 2:00:21 like vimu rafafhanib and then we have the ones that inhibit the cdk46 the palpo cichlib we also have drugs that can block hormones that influence this pathway and then we have monoconal antibodies that can block this pathway that should really give us an overall look at how we can use drugs to alter cell cycle regulation what about this weird little thing that I want to talk about here where it doesn't really influence the cell cycle regulation ution, but it does alter our immune processes and it does alter the angiogenic processes. All right, we don't want cancer cells to be able to evade our immune system. We don't want that. And so here we're going to take for example, let's say that we have a lymphocy, right? So let's say let's say it's a cancerous lymphocy. Let's say that this is a cancerous lymphocy. All right? And usually you'd see this in um we'll just use this as an example. This would be like non-hodkkins lymphoma because in Hodgekkins lymphoma they don't express the CD20. But here we're going to have this molecule and this is 2:01:21 called a CD20. So cluster differentiation. It's going to be expressed on these normal belymphosytes and then also malignant belymphosytes that are the non-hodkin lymphoma type not the Hodgekin with Rev Reed Sternberg cells. All right. Those are usually CD1530 positive CD2045 negative if you guys remember. But CD20 blockers, you're going to be using things like rettoximab. So retoximab, rtoxmab is a monoconal antibbody. And so if I give this drug, basically what it'll do is it will bind to that CD20. And when it binds to the CD20, here we go. Boom. Watch this. Ready? We're going to bind this puppy to the CD20. A couple different things can happen, right? One is I'm tagging it. And when I tag this, I can do a couple things. Let's say I tag this um CD20 with this monoconal antibbody. And when I do that, I open up an opportunity for specific proteins to kind of bind to it. You know, there's these uh proteins 2:02:22 called compliment proteins. And when they see these antibodies, they love to bind onto it. And when they do that, usually it creates like this little like thing called a membrane attack complex, which is this protein pore. It gets inserted into the membrane. And then what happens is water will be allowed to influx in and then what happens is this causes lic this literally causes the lis of these cells. This kind of mechanism is usually called some degree of like opssonization. So it's usually in some type of opsization or formation of a membrane attack complex. That's one way that we can kill these cancerous cells is we can have antibodies tag them and trigger them to undergo compliment activation. Right? So oxinization would lead to compliment activation, membrane attack complex formation. And you know what else? When you have these antibodies attacking this and then compliments come and bind to it, it it causes um macrofasages to get really really like they're like oh my gosh. It's like you take bread and it's 2:03:24 just bread. It's not that appetizing. You take bread and you slather some peanut butter and jelly. That's what the antibodies do. They create like a peanut butter jelly film which now when the compliments bind, macroofasages want to eat it. So it enhances fagocytosis and leads to membrane attack complexes. That's what this thing's called here. So you see this right here? This is called a membrane attack complex. We'll kind of represent that here. This little channel protein. The other thing that can happen is is when this binds it can trigger kind of like interest the pathways that activate different types of like proapoic genes things like the backax genes and when that happens it basically I'm not kidding it just triggers apoptosis of these cells so they start dying all right so also that's one kind of direct mechanism is it can activate proapoptoic genes and just initiate apoptosis in general another thing that can happen is that whenever we do this and we coat this, it can activate other types of killing 2:04:24 cells. And these are called natural killer cells. And natural killer cells when they kind of bind this, it activates them. And when natural killer cells are activated, they're nasty little buggers. And they release things like granzymes. And these gran like, "Oh, daddy, I'm I'm going to jack this cell up." And this gran get over here to this cancerous cell, trigger an intracellular cascade, activate those proteopotic genes, and guess what? Boom. and this thing going to be dead. So dead as a doornob. Now unfortunately this process here which leads to apoptosis but via indirect mechanism is called antibbody dependent cellular cytotoxicity. Heck of a name. But there's three downstream pathways that retoximab triggers. Optinization that leads to compliment activation apoptosis directly or antibbody dependent cyto cellular cytotoxicity. This is all going to lead to the death of these cancer cells. And usually which one? Lymphosytes. And so we use this one a lot. We'll talk about it later in um non-hodkkins lymphoma. Now that's one 2:05:26 way that we can activate our immune system. The other thing that we can do a little off topic is we can alter the angiogenic mechanisms. You know there's a drug it's called bevacisumab or bevacisumab actually I think they pronounce it. What happens with this is again it's a monoconal antibbody. You know these um these cancer cells they're sneaky sons of guns man. And they release something called veg f vascular endothelial growth factor. And they be pumping this thing out there. When that gets released what vef does is it binds onto the veg receptors. And when it binds onto the veg receptors on these endothelial cells it causes them to want to grow. And so I'm not kidding. It causes the endothelial cells to grow and they start sprouting off these like different kind of like vessels off of them and that's called angioenesis. All right, we talked about that in the beginning of the video which was about like six hours ago at this point. Right? So now when we talk about this here's what I want you to think about. If I give a drug like beismab that is a 2:06:27 monoconal antibbody and what it'll do is it'll literally bind to vef right. So when I give this veg F blocker, it is a monoconal antibbody. And so that monoconal antibbody will then bind with VEGF. When it binds with VEGF, can you then allow for this to connect the VEGF to connect with the VEGF receptor? No. Does this interaction take place? No. Can you tell the endothelial cells to start replicating and making more vessels? No. Can you deliver more oxygen to the cancer cells? No. So then all these cancer cells, they're depending on this increased blood flow. You're starving them, which is awesome. You starve them puppies. And that is what we want is we want to reduce the oxygen supply to the cancer cells and starve them essentially starve them of oxygen which can reduce their growth. So that's sometimes we'll give bevicismab we can actually give this one actually this one's given a colorectal cancer. So sometimes if we can't give 2:07:28 satuximab we'll actually give bevicismab. All right. All right. That covers these mechanisms which were kind of really kind of overviewing with kind of the immune kind of evasion process, the angioenic one, but this one really kind of we've repeated it multiple different times through the cell cycle regulation. Let's finish up the last part which kind of touches on this immune evasion process and how we can use drugs to really add our benefit of using our tea cells to kill these cancer cells with the immune checkpoint inhibitors. All right, so let's move on to immune checkpoint inhibitors. So these are again monoconal antibodies. Now, what's interesting about these is that they're really working to particularly, I'd say, turn the tea cell on, get it to be activated. Because if you guys remember, we talked about how, you know, these cancer cells, they can increase the expression of like their PDL1. They can cause the tumor cells to increase their expression of CTLA4. What if I could give come up with drugs to target things like PDL1 and PD1 and CTLA4? that would be a true benefit because instead of turning the T- cell 2:08:29 off, I turn it on and turn it against these cancer cells that trigger that cancer cell death. So, let's talk about that. So, antiPD1 and PDL1 inhibitors. Let's kind of break these down into their categories. So, let's first talk about the PD1 inhibitors and then after that we'll go over some of the names for the PDL1 inhibitors. All right. So, let's say here we have a T- cell. On the T- cell, what does it express? It expresses something called a T- cell receptor. That is what interacts with the antigen that's presented on this kind of cancer cell. The antigen is usually expressed on a MHC molecule and the MHC molecule interacts with this cluster differentiation protein on the T- cell. The other component on the cancer cells expresses something called PD L1. And then on the T- cell, it expresses something called PD1. We already talked that whenever these interact, what does it do? It turns the T- cell off. I want to turn the T- cell on. Don't get nasty, but that's what I want to do. So, I'm 2:09:30 going to give a PD1 inhibitor or a PDL1 inhibitor. With PD1 inhibitors, you can again remember it ends in MAB. The MABs portion of this is you can think about PMRO lizumab or nolumab. for PDL1 inhibitors. You can think about ATZO lizumab or dervalumab. Now again I don't want you to go too crazy. You don't have to like memorize all of these. I just want you to remember that these are the ones that end in MAB and that these can be PD1 or PDL1 inhibitors. Now if that is the case, if I give these drugs, the PD1 inhibitors when I give these monoconal antibodies will bind to the PD1, right? They'll bind to the PD1 or they'll bind to the PDL1. If they do that, essentially what is happening is is if you bind to the PDL1 2:10:31 with a PDL1 inhibitor, it won't be able to interact with the PD1. If you bind to the PD1 and you block it, you won't be able to interact with the PDL1. Essentially, you are inhibiting this connection. This is the very connection essentially son of a gun that does what? Turns the T- cell off. If I block this connection, what will I do? Turn the T- cell on. So that's what I want to do. I want to give PD one inhibitors or PDL1 inhibitors. And this is essentially going to do what? They're going to be monoconal antibodies that bind PD1 or bind PDL1 and inhibit this interaction. Essentially, what will that do? That'll take and turn the T- cell on. If I turn this TE-C cell on, that is going to trigger the TE-C cell to be able to cause death of these 2:11:31 cancer cells. So, it'll then trigger cancer cell death. And that's what we want. We want these TE-C cells to fight the battle, but we just need to help it by giving these immune checkpoint inhibitors. Now, in the same concept, but we're going to be a little bit different in the mechanism. You have anti-Cta4 antibodies. Now, these usually the the one that I like to remember is epilimumab. And again, just remember the MAB portion with this. It's again, it's a monocclonal antibbody. But then you got to talk about, okay, how is it really working? Well, here we're going to have this blue cell. This is a antigen presenting cell. This is a T-C cell. Again, think about the connections that we have going on here. What is this red one here? This is a MHC complex. Probably type two. There's an antigen. What's it binding with? The T- cell receptor, right? Then cluster differentiation protein from the T- cell interacts with the MHC. Over here in green on this APC, you have what's 2:12:32 called B7. This black protein is called CD 28. And this blue one is called CT4. Whenever CTLA4 is bound to B7, it inhibits the T- cell. Whenever CD28 is bound to B7, it leads to co- stimulation and activates the T- cell. I want these to interact. So what do I got to do? I got to bind up the CTLA4 so he can't interact with the B7. So that's what I'm going to do. I'm going to give this drug the anti-CTA4 inhibitor and by doing that I'm going to give these monoconal antibodies and these monoconal antibodies are going to go do what? They're going to bind all over this thing and now it's not allowed to interact with B7. So who now is open to come to the party? CD28. And because of that, this allows that co-stimulation signal that we've talked about, son of a gun, all the way back to immunology when we talked about 2:13:32 co-stimulatory signals. This thing gets activated. So then what happens? We activate the TE-C cell. We turn on the TE-C cell. If we turn on the T- cell, what will it do? It'll trigger this cancer cell death that we want. So when we talk about ways that we can target different cancer cells, think about it, man. We can target the cell cycle by targeting maybe the what Sphase. We want to target them as we're trying to incorporate making nucleotides or taking the nucleotides and incorporating into the DNA. We want to block DNA replication by doing it at the super coil by also potentially maybe intercolating by forming covealent bonds by generating free radicals. We want to then inhibit let's say have we make proteins that are essential to separate the DNA chromosomes or the chromosomes which is the genetic material between the two cells. We can use microtubial inhibitors if we want to be able to come up with ways to inhibit the downstream 2:14:33 cascades that push the cells into the cell cycle via the CDK pathway. We can use tyrrosen kynise inhibitors. We can use jack inhibitors. We can do her two pathway inhibitors. We could do what else? Uh you could do map kynise inhibitors, CDK46 inhibitors. If I want to use hormonal therapy, I could use things like G&RH agonist, G&RH antagonist, serums, aromatase inhibitors, anti-androgens, the list goes on. And if I want to activate the immune system and have it fight my battles for me, I can give things like rtoximat or I can give things like CTLA4, antiPD1, antiPDL1 inhibitors. And if I want to starve the cancer of its blood supply, I can give things like bevicism. You see how these are so many different mechanisms that we can use to target and that doesn't even believe it or not we didn't talk about all the anti-neoplastic agents that you could talk about. I just talked about the ones that you probably could see on the exam and the ones that really make sense with these mechanisms. What I want 2:15:34 to do is because believe me I understand the overwhelming feeling feeling that you probably have right now with all of these different agents and their mechanisms. Let's go through this step by step. Let's do a quick review of all of these looking at it holistically as a quick summary and then from there we'll move on to the next step which is talking about the indications. when do you give this drug? Or more likely because patients who have cancer, we're treating them with combination chemotherapy, we'll talk about those drugs because you'll learn later when we talk about the basics of chemotherapy. When you give a drug, you can have, let's say you have a tumor, one gram tumor in your lung. When you give that chemotherapy, your goal is to have that log kill hypothesis to kill a constant fraction of cells with each dose until you shrink the cells down to nothing. That's curative chemotherapy. Sometimes you can do that. You can treat a cancer with just chemo. Sometimes you can't do it completely and you need a little help. So then you got to cut the tumor down, debulk it. That's surgery. And then afterwards you have some residual 2:16:34 tumor cells left. You give chemo until they reach curative points or remission. Right? So that's curative chemotherapy. Sometimes you have a patient who has a mass that's so big it's spread to other areas of the body. Your goal is not going to be getting rid of it. It's going to be reducing the size of it and at least kind of slowing the progression. So if you can decrease the size, cool. But if you can at least prevent its progression from getting bigger or give them a little bit of a better quality of life in the meantime to reduce symptoms from the size of it, that's what we call palative chemotherapy. And so we'll talk about all that when we get into the combinations and different therapies. And then once we do that, let's come back and let's talk about some of the adverse effects because when you give these drugs, you have to consider what you need to monitor for. Let's say that we kind of go through our cell cycle. Well, obviously we have some cells when they go through the cell cycle, they don't kind of just go back in and go through the replication process. Some of them kind of just live in that Got phase where they just kind of they rest, 2:17:26 right? They're in that quiescent phase. Some of them though, they they do they actually run right into the next part where we're actually going to start getting ready for that genetic material to get ready to be replicated. We're going to start kind of beefing up some of our organels. We're going to start getting increasing protein synthesis that we need during that G1 phase. Then what happens is we're going to get these chromosomes ready and we're going to go ahead and replicate them. So we're going to undergo that DNA synthesis process that occurs in the Sphase. Now after we replicate that, we got to start getting a lot of proteins and enzymes ready that are going to help to allow for the separation of the cell from one like overall like cell to two daughter cells. And so that's when we kind of start getting the actual cell ready to do that. And that's in that G2 phase. What happens is after this cell kind of gets ready, we're then going to start going through the steps of separating the cell. So we're going to go through proase, we're going to go through metaphase, anaphase, tilophase, and then we're going to pop out another cell. So you see how from this we start with one 2:18:27 cell and we kind of continue throughout this process and we can pop off two new daughter cells. That's the goal of the cell cycle. So what we know about neoplasia, what we know about cancer is that these cells continue to really really drive themselves through the cell cycle very very aggressively. If there's ways that we can come up with drugs to target these cells at maybe specific phases or at any phase of the cell cycle, that is the goal of a lot of these anti-neoplastic agents. Let's kind of review them. So real quick before we do that, just you have to remember there is another point. So there is checkpoints along the way. One that's really really important is the G1Sphase checkpoint. That's really I'd say highly highly dependent upon something called CDK cycl dependent kinases. And so it is important to remember those those work really really importantly um in that G1Sphase checkpoint and we'll talk about a lot of different drugs that work at that point as well. Let's dig into it. First thing I need you guys to remember is that we have purines. These are a specific type of 2:19:27 nucleotides. We have perramdines. These are spec I'm sorry nitrogenous kind of bases. And these are going to be helpful for making nucleotides. So we have purines and perramdines. What's going to happen is is we use a lot of different enzymes in these processes that we talked about to make ribboucleotides which are basically as you see here a phosphate group a ribbo sugar and then the appropriate purine or perramdine. All right. Now the enzymes needed there is a lot of them just a couple of them that we talked about is like PRPP synthetase. Another one is called adenosine diaminise. There's another one called dihydropholate reductase and then there's what's called thyolate synthace. These are some of those enzymes that we talked about in individual portions that are critical for taking purines and primitines and helping to make ribboucleotides. Now ribonucleotides they're very very important. They're a base structure that all we want to do is take this hydroxal group and get rid of it and turn it into a hydrogen and that converts this into a deoxy ribboucleotide. 2:20:27 This process is dependent upon specific enzymes and that's specifically what we call riboucleotide reductase. The other thing is that we want to take each one of these deoxxyribboucleotides in the form of adenosine, guanine, thymine um and cytosine and really incorporate them piece by piece into the DNA and the person who facilitates that is the DNA polymerase enzyme. And then the other thing is that we don't want the DNA to over twist and super coil. So we use topo isomeases type one and type two to help to maintain that DNA structure. And then what we know that DNA can do for us is that we can transcribe it to make RNA. And then RNA can then be utilized in the process of translation to make proteins. And one of those proteins that are super critical to the cell undergoing its whole proliferation process is microtubules as a specific example here. So now I kind of want to take this generic diagram and really apply how a lot of our anti-neoplastics works in more of a simple way if you want a quick reminder. 2:21:29 Let's go back. Let's talk about the S-phase inhibitors. That was a lot of your anti- metabolites and there was a bunch of them. If you guys remember six mermer caperine and aathioprine, they were really really powerful kind of drugs that can help to create these intermediates, right? The the the thio kind of puring kind of like analog and what's important about that is that there was really critical to inhibiting the PRPP synthetase and the adenosine daminase, right? So it's really crucial with the IMP process that pathway and so we're inhibiting that and what happens is is that's going to inhibit the purines being converted into ribboucleotides being converted into deoxxyribboucleides you get less DNA that's being made and if you can't make DNA you can't replicate the cell that's a really cool process there anti- metabolites like methtoresate 5FU which is your five floruricil these were critical to playing a role with the dihydropholy reductase that's specific to the methtoate and the 5FU was specific to inhibit the thyolate synthes 2:22:30 and these were critical particularly if you know methtoresate it's important within the folate pathway now folate pathway does help to make purines and it also is really important in making perramitines like thyolate and so that's really really important to remember that so when we inhibit these enzymes we then essentially inhibit the formation of perramdines and if you can't make perramditines you can't make ribonucleotides and you can't make deoxxyribboucleides you can't make DNA and you can't replicate the cell other drugs that we talked about like hydroxyurora and gyms. These are drugs. So hydroxyiora is a pure ribboucleotleide reductase. Jimcytoine has multiple types of functions. It's just one of its additional functions is it can inhibit riboucleotide reductase. What did that enzyme do again? It took a hydroxal group from a ribboucleotide and then converted into a hydrogen group. If we inhibit that enzyme, we can't do that. We can't make deoxyibboucleotides and we can't incorporate them into the DNA. If we can't make DNA, we can't make new cells, my boy. Now, another anti metabolite groups is going to be 2:23:31 citarabene. And these ones are cool because we can kind of group these together. Jimcytoine, which we already talked about is right here, which has a RNR inhibitor. Another one is cladroine. And then lastly is fluorabine. These are what we can kind of refer to as nucleotide analoges, if you will, in the sense that what they can do is they can kind of be incorporated as like a fake nucleotide. All right? They come in as nucleide analoges and then what happens is once you try to add them into the DNA, they go through like a phosphorilation process. Once you try to incorporate them into the DNA, the DNA polymerase can't click. So it takes the the actual the drug the siterabine the gymine the cladrobine the flutarabine they're going to act like a nucleotide they're going to get clicked into the nucleotide prior to make a DNA strand and then whenever the DNA polymerase goes to grab the next kind of nucleotide it can't click it together and that terminates the DNA replication process which is I think really cool also some of these 2:24:31 especially gems um and even citarabene can inhibit and some of them a lot of them can inhibit DNA poly polymerase itself. So they can inhibit it directly or indirectly by inhibiting DNA polymerase to add another nucleotide onto itself. So that's a really cool concept to think about. Now you see here that antimabites again a lot of them and we can think about them in this particular way or we can think about them in this diagram that we talked about. It's very simplistic but these really help to inhibit the cell within the Sphase when DNA replication is crucial. And so that's going to help to inhibit a ton of cell replication, which is great in a lot of cancers, especially kind of like any cancer that is involving the bone marrow. Um, and we'll go through a lot of indications and when these kind of drugs can be utilized, but these are really, really powerful. And so because of that, they can also affect any other cells that are highly replicating. So like epithelial cells, your bone marrow cells, they can affect any kind of mucosal tissue. And so that's why you get a lot of side effects unfortunately with these drugs. But another way to group them as we 2:25:32 talked about is that methtoresate is a folate antagonist. Six mercapurine as aopene, cad cladropene and fluarabine specifically are inhibiting the purine pathway and then your perimeonists are going to be your five floor uricil citarabene and gyctoine and then your ribonucleotide reductase inhibitors is primarily hydroxyora with the addition that as we have asterisks here gyctoine can also be a ribboucleotide reductase inhibitor. All right, that's your anti metabolites. That's the beefy group. Let's now move into another group. When we think about these topo isomease inhibitors, they're they're actually pretty cool how they kind of work. So again, you have topic, teniposite, arinit, and topic. And again, we talked about this a lot. All I want you to do is remember how are they kind of like working in this process. They're going to inhibit topo isomease enzymes. Topo isomeases are critical for the DNA super coils. They're kind of preventing the DNA super coils. That's how the the enzymes generally work. If we inhibit those, we we allow for these super coils to either get worse or we incorporate a lot of DNA fragmentation into the process. And essentially what happens is 2:26:32 whether you fragment the DNA or you inhibit the actual kind of pre you basically continue to induce super coils if you will that inhibits the DNA replication from occurring at the replication fork process. So either way you're inhibiting the DNA formation. Another thing I want you to remember is anti-tumor antibiotics also work at this level. So this is going to be like doxy rubicon, donor rubicon, dctenomy, bleomy. These are going to inhibit the DNA from actually being able to replicate or at least form. The mechanisms if we're really being particular again doc rubison, don ruben, takenomy, they really have that threeprong mechanism. They can act as an increasing reactive oxygen species. They can kind of intercolate kind of the DNA and form like weak bonds between the nucleotides that inhibits the replication fork and the DNA polymerase from moving down it. And on top of that they also have topoisomease type 2 activity. So they can even kind of like again cause the topo isomease to cut but not to be able to rely and that's where you get that fragmentation. You also again continue allowing the super coils 2:27:33 to occur. All of these things inhibit the DNA from being properly replicated. Another thing is alkalating agents and so this is your cycloposomide phosphomide melphan teosolomide cis platin carboplatin oxaloplatin. All of these are primarily working to kind of like get into the DNA and to cross-link. They really form very strong kind of like cross-linking between the actual nucleides whether it's interstrand or intrastrand. And and the problem with that is then again it's the same thing. You can't allow for the DNA polymerase to move down the DNA and allow for it to continue to replicate and allow for that process to occur. So that's one thing. You don't allow for the replication forks to be opened up. All of these things they inhibit DNA from being formed. So all of them kind of work at that step as a simple way of remembering it. But then to kind of take it to the next level, topoism type one inhibitors exist. That is technically the arenotic and topin. And they really only work best in the Sphase. Topoism type two inhibitors as you can see colorcoordinated here. This is a topocid and tenipocide. They can also work in 2:28:33 the Sphase, but they really are more prominent in the G2 phase. And then lastly is bleomy. It's one of the only other kind of anti-tumor antibiotics that are listed that really has a cell cycle specific phase that it works in and that works in the G2 phase. As you can see here in all of these like colors, anti-tumor antibiotics like doc rubicon, don rubicon, titenomycin, cyclophosamide, iphosomide, melphan, teosolomide, all the platinum compounds, these are cell cycle non-specific. So anti metabolites are sphase specific. Topisomease type one is Sphase specific. Topisomease 2 is G2 phase specific. Bleomy is is G2 phase specific. All of these other agents that we have right here that are not bleomy in this scenario that are kind of in this darker gray black color. These are cell cycle non-specific meaning they can work at any phase. They can work at G1 phase, Sphase, G2 phase, Mphase. They heck they could even work in the G not phase. It doesn't matter. That's an important 2:29:34 thing to take away from that. The last one that is a cell cycle specific agent is going to be your microtubial inhibitors. This is going to be venristine, vinlastine, dositaxel, pitotaxel. And what they do is they inhibit particular proteins in this kind of like overall simplistic diagram. Remember they inhibit the microtubules. They either inhibit the polymerization reaction or the depolymerization reaction. The whole point of that is that you can't allow for the cells to go through their proper metaphase anaphase tilophase process. And so if we really want to be particular microtubial inhibitors can be broken down into two groups. The vinka alkyoids which is your vinristine your vinlastine and then the taxines which is your dosataxel and t pleataxel. And the thing to remember about that is that the vinkas those are working to inhibit more of that kind of polymerization and then the taxes are working to inhibit more of the depolymerization process. That really gives you a good understanding of the cell cycle specific and cell cycle non-specific agents that can either work 2:30:36 in a specific phase or any of these phases. What about agents that maybe work more particularly at like the G1Sphase checkpoint? So we're kind of going to be a little bit specific but also kind of indirect and we kind of talked about this a lot where we have something called CDK4 and six cycl dependent kynise type four and type six. Now what I want you to remember is there was a lot of different receptors that were on a cell surface and especially in this particular scenario a cancer cell. You have things like Jack 2 receptors, epidermal growth factor receptors, you have ALC receptors, you have BCR aable proteins. So they're not really receptor. They're kind of a non-receptor tyrroscene kynise enzyme. And then you have her two receptors. You also have estrogen which is really really important in some types of tumor cells and they work on particularly estrogen receptors. These are usually intracellular. They are not usually extracellular as we've seen with these particular scenarios. And then you also have and androigens. Androigens are really important in certain types of tumors as well, especially like prostate cancer. Um, and they also have intracellular receptors that they bind 2:31:37 to like androgen receptors. What you'll notice that there's a common theme and that all of these usually end um at least in some way, shape or form on cycendent kynise type four and type six. And that's really really important because what I want to do is I want to go through the left half and I want to show you how they lead to cycl dependent kynise. Then I'll go through the right half and show you how they lead to cycl dependent kynise. So first thing here that I want you to remember is that there's three intracellular pathways that are super crucial to then activate cycl dependent kynise. On this left half of the illustration, let's kind of go through this one is called PI3K and AKT. This is an intracellular pathway that is really critical that h helps to be able to activate specific transcription factors that induce the cell to undergo growth. that activates protoonco genes, inhibits tumor suppressor genes and essentially cause the cell to go through its proliferative processes. Another one is called the signal transducer activator of transcription. Whenever you have these receptors or these pathways, they stimulate this transcription factor to do the same thing. Stimulate the 2:32:34 protoonco genes inhibit the tumor suppressor genes. And then also you have what's called raz rafmech. This is all going to lead to your map kynise pathway and that's again going to activate particular transcription factors that stimulate protoonco genes and inhibit the tumor suppressor genes and push the cell to go into its replication process especially in cancer cells if all of these are hyperactivated right so let's say that a person is going to be you know they receive some type of like epidermal growth factor and it binds to that receptor it can then work to increase this pathways um alk if you have some type of a growth factor that binds to this tyros tyroscen kinus receptor that's usually has an alk rearrangement that can also increase this pathway if you have things that bind to bcrable usually things like ATP it activates this enzyme and helps it to then push it into this pathway or if there's mutations in that enzyme which causes it to be constituently active that can then push it to kind of activate these pathways if there's lians that bind on to the her two receptor that can 2:33:35 stimulate these three pathways now jack 2 is a a little bit more specific. So that's a Jonis kynise. Whenever it's activated by specific growth factors, it can really inhibit more of a particular pathway. And then again, whenever you have a lians binding to the Jack 2 proteins, again, this is going to trigger an intracellular pathway that's going to activate again that stat, that signal transducer activator of transcription. Here, what I want you to do is we're going to see kind of a common theme. Estrogen whenever it's in high amounts can bind to the estrogen receptor. And when it binds to the estrogen receptor, it's going to activate a specific enzyme. Androgens's in high amounts will bind to the androgen receptor. and when high amounts are going to activate this particular enzyme. Whenever you have these growth factors and in patients who have maybe specific types of mutations in these receptors, they will then increase the these three pathways. All of this will converge onto one thing and that's this enzyme complex called CDK46, right? So there's cycl dependent kynise 4 and cycl dependent kynise 6 and these are usually associated with a cycl 2:34:32 enzyme. Once this kind of activates this enzyme, this enzyme is going to do what a kynise does. It's going to phosphorolate proteins. And so what it does, it puts phosphate groups onto the retinol blastoma protein. Retinol blastoma protein. Think about it basically it holds E2F. Normally if you add phosphates to it, its mouth opens and E2F goes from a bound form to a free form. Whenever you have free amounts of E2F, this acts essentially like a transcription factor that then goes down, activates those protoonco genes, shuts down those tumor suppressor genes, and then does what? Causes the cell to go through excessive replication cycles and grow. And that's how you end up getting cancers. So that's why patients who have specific types of jack 2 mutations, they're predisposed to specific cancers. People have mutations in these receptors, they're predisposed to specific cancers. her too predisposed and conditions of where you have high amounts of estrogen it predisposes you to the cancer growing or getting worse high amounts of androins conditions that ex either increase your exposure risk or progression of that particular cancer so 2:35:34 then what we need to do is is kind of like figure out how can we kind of insert these drugs along this process to inhibit these so let's kind of think about that what I want to do is I want to again tell yourself the cell can go into a gene phase where it just kind of rests right doesn't really do anything it's not going actively kind of replicating or it can decide to go into the replication cycle and proceed to the G1 phase. Then it's going to replicate its DNA in Sphase. It's going to get ready to start processing the mitosis in the G2 phase and then it's going to run through mitosis and make another cell. Again, these agents that we're going to talk about aren't cell cycle specific. They're kind of like non-specific, but they really tend to work at checkpoints in an indirect manner. And that's what I really want to talk about. So one of these could be Jack inhibitors specifically a jack 2 inhibitor. This would be an example like roxalitive and it's really going to inhibit what what's going to inhibit the jack 2 from being able to send this signal and if you don't send that signal what's going to happen is you're not going to have a increase in the stat. You can give 2:36:33 tyrroscen kinus inhibitors that actually work against that eGFR. This would be like oertinib. If you shut down that receptor you don't send those signals. Um, if I use things like an alt tyroen kinus inhibitor like altctanib, that's going to shut down that receptor and it's not going to send those signals. If I can use things that inhibit the bcable enzyme, I can give by bcrable tyrroscen kinus inhibitors like amatanib and that's going to again shut down that enzyme from sending the signals. If I can give things that are her two inhibitors, this would be something like trstusimab that's going to shut down the signals going from that receptor. And the beautiful thing about this if you guys remember is this is a monoconal antibbody. These are protein kinase inhibitors. This is a monoconal antibbody. Again, you see a pattern here that if we're inhibiting these receptors, it's going to shut down these intracellular pathways. If we shut down these pathways, we then drop the levels of PI3K, AKT. We drop the levels of stat, we drop the levels of the RAZ, the raft, the mech. Now, these enzymes have the ability to go and work on the DNA themselves. But in this pathway, if you 2:37:33 don't have enough of these, are you going to be able to stimulate CDK4 and six? No. And that's a problem. One other drug that I want to mention is that this RAZ, Raph, and Mech, we can actually give drugs that directly inhibit the raph and that's called your RPF inhibitors. That's vimarafhanib. So that can directly inhibit this particular pathway with emphasis on the raph. Either way, you get the point. If I don't have these guys that are in high amounts and they're actually in decreased amounts, they're not going to be able to stimulate CDK4 and 6. So that that CDK4 and six level is going to become less active. We're going to inhibit it theoretically. Now another thing that's really important is that we have drugs that can directly inhibit CDK4 and six and that is usually your CDK46 inhibitors. This is like your cichlids right? So palpichy and what happens is they can directly inhibit this enzyme. So these are indirectly in some way inhibiting this enzyme. This one is directly inhibiting this enzyme. Now the beauty of this is that if you inhibit this enzyme what happens? You no longer phosphorolate retinol blastoma 2:38:33 protein. Can it release the E2F? No. What happens to the free levels of E2F? It drops. What happens to you now stimulating protoonco genes? Nope. What happens to you inhibiting tumor suppressor genes? Nope. So now in this scenario, you're not allowing for the cell to replicate and you're preventing the cell from continuing to evade apoptosis. That's going to shut down that cell growth. And that is a way that we can kind of control the cancer. All right. So now again what we kind of see out of this is that if we are theoretically inhibiting this cell in that G1 kind of Sphase checkpoint, that's really where it's working. It's not working in the G1 phase. Again, it's working in the G1 Sphase checkpoint. Then what we're going to do is we're going to theoretically inhibit this cell from going through the Sphase, the G2 phase, the Mphase, and then we're going to drop down that cell proliferation the simplistic way. Right? So that's what I want you guys to think about here. Now, let's move on. Let's can now cover the right arm. So we went through the left arm. Let's go through the right arm of this scenario. Again, I want you to remember that androgens, they are 2:39:31 capable of doing what? Being converted into estrogen through what enzyme? Aromatase. And that's a really important thing to remember. And then we know that estrogen can bind to estrogen receptors and they can act on CDK4 and six and they kind of stimulate that pathway. What if in that scenario I, you know, I think about ways that I can target specific areas. So, I'm going to use something called serums. These are your selective estrogen receptor modulators. This can be things like tmoxifen and even technically to a degree relaxophane. And what happens is these are going to help to inhibit the interaction between estrogen and the estrogen receptor. So if you inhibit that, you essentially inhibit this ability to do what? Stimulate the CDK4 and six. Right? Another drug that we can give is G&RH agonist. Um and this is usually going to be things like lupide. And then we have G&R antagonist which is going to be like degellexics. And what these are going to primarily do is they're going to inhibit. They do it in specific ways. So GRH agonist is going to lead through a kind of a process where it increases FSH and LH and that's then going to go and cause an increase 2:40:29 in estrogen, but then there's going to be a negative feedback that then shuts down the FSH, shuts down the LH and eventually drops the estrogen. That's how G&R agonist would work. G&R antagonist, they're going to specifically work in what way? They're going to directly inhibit FSH and LH and that's going to lead to a drop in estrogen. The combination of both of these do what? They drop estrogen. If you drop estrogen, then what? Can it activate a receptor? No. Not if you don't have enough of it. Can it then stimulate the CDK4 and six? No. And so that's a problem. Aromatase inhibitors are another one. This is usually things like anol, letol. Um, and what they do is they inhibit the aromatase enzyme. If you inhibit the aromatase enzyme, can you convert androgens into estrogen? No. So you effectively lower the estrogen levels. You don't have enough estrogen to bind to the receptor. Can it activate the CDK4 and 6? No. Now you get the point that all of these influence a drop in estrogen. that drop in the the effect of estrogen activity or the ability of estrogen to bind to the receptor leads to an inhibition of the CDK4 and 6. Anti-androgens are another one that we 2:41:28 can use. And what they're going to do is they're going to block and from binding to the receptor and that's usually like inolutamine. And what happens is if you do that, you don't allow for androgen to bind to the receptor. That complex is no longer able to help to activate the CDK46. And so it's essentially you're inhibiting CDK4 and 6. If I inhibit CDK4 and 6, what happens again? We know that we don't phosphorolate retinoplasto. We don't release the E2F. We then continue to inhibit protoonco genes. We stimulate the tumor suppressor genes and we stop the cell from continuously growing. And that is going to stop that cell proliferation. That's going to help us with these particular cancers. Now again, we're going to go through the indications in a little bit, but I think what's kind of cool about this is that you can kind of think about how these kind of like drugs work. And so I want you to think about this. Usually inhibitors are great within melanoma. Jack 2 inhibitors are really good within CA patients who have something called polyythemia vera. Um it also is good in conditions like myo fibrosis and again these are usually a myo proliferative neoplasia and what we'll see is that 2:42:26 lung cancer these really respond well any kind of eGFR tyroscen kynise inhibitor and al tyrroscen kinus inhibitor if there's specific mutations present they will respond well in patients who have specifically non small cell lung cancer we know that BCR able tyrroscen kinus inhibitors are really good in those patients who have the Philadelphia chromosome the 922 transllocation because it basically creates a a mutation in this BCR aable and so really really good in CML and in some small cases of patients who have AML with the 922 transllocation it can also be utilized uh her too is really it's can be beneficial in metastatic gastric and esophageal cancer but what we commonly know it utilized in is it's going to be breast cancer now we also know that breast cancer is really really important because you can use breast cancer as a way of saying we can use CDK4 and six inhibitors we can use ser we can use aromatase inhibitors and obviously in these certain scenarios it depends depends upon if they're estrogen receptor positive, progesterone receptor positive, if they have metastatic scenarios, if they're premenopausal, post-menopausal, if they have her two 2:43:26 positive breast cancer or not. There's a lot of factors and again we'll talk about that a little bit later. And then for your G&R agonist and your antagonist and the anti-androgens, these are really going to be beneficial in patients, especially those who have things like prostate cancer. And so that's something that I want you guys to think about in this potential scenario. Another potential thing I want you to think about is we talked on the whiteboard about immune evasion. We talked about angioenesis. Let's kind of just have a quick little recap of that. What we know is that these cancer cells again, they're releasing something called VEGF, right? Vascular endothelial growth factor. And what that does is that helps to activate those endothelial cells of nearby blood vessels to start making more going through the replication and making more endothelial cells which then kind of sprouts these little branches off of the artery and that's called angioenesis. Whenever they bind to that receptor, they promote a formation of new blood vessels. If you have more blood vessels, you theoretically have more blood flow. More blood supply to a cancer, just allows for that cancer to 2:44:17 continue to keep growing and growing and growing. Now, what if I give a VEGF blocker? And that's something like bevicism. It's a monoconal antibbody that binds to VEGF, prevents it from binding to the VEGF receptor. If I can't bind to the VEF receptor, I can't undergo the angioenesis process and I can't actually increase blood supply. So, theoretically, I starve the cancer cells and that may over time promote cancer cell death. theoretically right now another concept here is that some patients especially have cancerous cells I want to be specific and say cancerous lymphocytes cancerous lymphocytes sometimes what can happen is they can express specific types of proteins on their surface right especially CD20 and we see this a lot in patients who have what's called nonhodkins lymphoma when you express CD20 we actually use a drug called rettoximab which is a monoconal antibbody that can bind to the CD20 and then it can promote three mechanistic responses one is it can promote a compliment fixation which can lead to oxinization or worst case scenario it can lead to the compliment proteins promoting what's called a 2:45:18 membrane attack complex. Membrane attack complex is a pore inside of the actual cell that then allows water to rush in and induces licis of that respective cell. On top of that, it can actually just initially activate apoptoic mechanisms in the cell may undergo apoptosis. And on top of that, it may then activate specifically natural killer cells to then see these particular antibodies bound to the CD20 and it may induce it to undergo a process where it releases things like granzymes. And when it releases those gran then triggers the cell death process and that may cause these cells to die. So that's one way where we can use rettoximap to treat a particular cancerous uh condition especially in situations where you have lots of cancerous lymphosytes like in non-hodkins lymphoma. All right. So the next thing I want you guys to think about is when we have these cancer cells you know these cancer cells are finicky. They're kind of smart where they can kind of change expression um of specific molecules right on their surface. And they can also change the expression of certain molecules on even other cells like tea cells. And so they're kind of cool. Uh terrible thing but you know we 2:46:18 have ways of being we figured it out. we're a little bit smarter than the cancer cells kind of right. So cancer cells what they can do is again they express something called PDL1 and a lot of the times what happens is that they can really overexpress that um in a significant amounts and you'll see why in a second again we already kind of talked about this with a nice little recap. Uh MHC complexes are pretty common especially more of the type one um on their surface they usually present with some sort of an antigen and then T- cells we know that they interact with usually these two proteins in specific ways. So PDL1 interacts with PD1 and then T- cell receptors usually interact with the antigen and they have a CD protein that interacts with the MHC complex. Whenever you have this interaction between the PDL1 and the PD1 when they click together it kind of turns the T- cell off and it has no desire to want to do anything with this cancer cell. So it's kind of smart in that way that if a cancer cell expresses a lot of the PDL1 it creates a problem. Another thing that TE- cells do is they express something called CTLA4. And what happens is that's a normal molecule, but 2:47:13 cancer cells, they lead to the overexpression of CTLA4. TE- cells again, we know they express T- cell receptors and we know they express something called CD28. What I want you to remember is that CTLA4 and CD28 are kind of like competitors for another protein on a cell that's going to pop in called an antigen presenting cell. Antigen presenting cells, they interact, again, we already know uh MHC complex, which has a little antigen on it. Uh usually these are type two. They interact again that antigen with the T- cell receptor and then there's a CD protein usually that interacts with the MHC complex. But here's the big competitor. This is called B7. B7 has an opportunity to interact with CD28 or CTLA4. If CTLA is present in high amounts, it's going to have a higher affinity and they're going to interact. When they interact, the T- cell is then what? Turned off. But whenever B7 and CD28 interact, the T- cell is turned on. So that's what we want to kind of think about here. So again, PD1, PDL1, when they interact, the T- cells turned off. When CTLA4 and B7 interact, the T- cells 2:48:15 turned off. What I want to do is I want to come up with ways of being able to inhibit this interaction to turn the T- cell on. And I want to inhibit this interaction to turn the T- cell on. So how am I going to do that? Well, if I give a PDL1 inhibitor, what it'll do is this is a teslammab and dervalamab. These will then come in and they'll kind of bind. their monoconal antibodies and they'll bind to the PDL1 and block the PD1 from being able to kind of click in. So that's one way. Another one is I could just give a PD1 inhibitor and this is going to be things like pimplyab, niblamab. They're going to come in act as a monoconal antibbody and bind to PD1 and inhibit PDL1 from clicking into it. That's going to inhibit that interaction and that theoretically would then allow the T- cell to be turned on and then it's going to want to kill the cancer cell. Right? Another drug that we can give is a CTLA4 inhibitor. If CTLA4 is increased in expression on cancer cells, if I block it with an antibbody like epilemmaab, what's going to happen? Well, then it's no longer going to compete with CD28 with B7. So, who's going to interact a lot? The CD28 and the B7 will start to interact. And if 2:49:17 they interact, at least the B7 interacted with the CTLA4 and that leads to a co-stimulatory signal that leads to an activation of the TE-C cell and that T- cell going to be ripping them cancer cells up. And that's what I want you to remember is that the goal is to inhibit that interaction so we can turn the T- cell on. And the same thing with the CTA4, inhibit that interaction so that we can turn the T- cell on. All of this will then allow the T- cell to induce that cancer cell death. This is a good recap of all of these mechanisms that we talked about on the whiteboard in great detail. I hope it makes sense because now what I want to do is I want to move into what are the indications. Why do we even give any of these particular anti-neoplastics? Well, I want you to kind of think about it in groups. Let's say I talk about hematic malignancy. So something like non-hodkin lymphoma we use a bunch of different chemotherapy agents sometimes to target these cancer cells and a common one is the archop regimen we talked about that in lymphoma and that's usually going to be consisting of what it's retoximab right that's going to work against that CD20 molecule cycloposomide 2:50:15 all right we talked about that as more of that alkalating agent hydroxy donor rubin which is doc rubisonin that's one of your anti-tumor antibiotics ankovven which is also vin christristine which is one of your microtubial inhibitors and then prednazone prennazone actually naturally has a way of suppressing uh cancer cells as well and so it has an imunosuppressing capability and it's actually going to be used in certain types of scenarios of cancer as well. So you can see how we're using multiple different agents to target one cancer. Hodgekilyoma kind of a similar concept. You can use something called an ABVD regimen and that is usually going to be adriomy bleomy. So bleomy is actually one of those agents which is an anti-tumor antibiotic vinlastine which is a microtubial inhibitor and decarbazine right which we didn't talk too much about this one but again you get the point is that these have the capability of having multiple different agents to target a cancer. It's very common to have combination chemotherapy. Chronic lympositic leukemia actually responds pretty well to a BTK inhibitor which we didn't talk a lot about but it's called a brutin but it kind of 2:51:15 works similar in that it actually is going to have the capability of inhibiting a very specific receptor the bruty kinus that's actually present on lymphocytes in these chronic lymphocitic leukemia condition. All right chronic milo leukemia we kind of talked about this one as a high yield one. Do you guys remember it was the BCL inhibitors. All right. So specifically the amatanib is a really good one. Acute milo leukemia we actually can use combination. Yes. If they have the 922 transllocation we can use this as well. But the big thing to remember is that we like to use caitabine and don rubes. You're like okay how do I remember that? Well a music lover a music lover CD is like maybe a helpful pneumonic for you. So again aml with a music lovers in CD sitabine and donor rubicon. Acute lymphoplastic leukemia is another one that we want to talk about and this one actually can have combination chemotherapy as well and usually that's venristine predinazone asparagenase and donor rubicon. How do I remember this one? Oh all very powerful agents destroy. So again you can remember that in all we're going to use vincine we're 2:52:15 going to use predinazone we're going to use asparagenase and we're going to consider donor rubisin in certain types of scenarios. uh intratheal methtoresate is utilized in acublas leukemia prophylactically to prevent the meningial leukemia because it's a very high risk and it's also has potentially for high mortality and so we like to get intratheal intratheal methtoresate as a prophylactic measure to prevent meningial leukemia all right so again all in the meningis you can remember intratheal methtoate again it's really important one out of all of these to remember uh again I think it's important to remember these drugs just but it's more kind of a giving you a point the real important Important to remember for all is that we have to give intratheal methtores as a prophylaxis to reduce the risk of meningial leukemia. Multiple myyoma. This is one that we didn't talk about a ton. Again, it's one of those plasma cell disorders where you're can producing tons and tons of plasma cells that lead to a lot of amunogloabbulins being produced. But what we like to do with this one is we like to give on something called bortesmib lolyomide and dexamethasone. 2:53:14 We didn't talk about this a lot, but bortezmib is actually kind of one of those proteosome inhibitors. And linolyomide is an amunosuppressant along with dexamethasone. And again you can remember dog loves bone dogs love bones. So dexamethasone is for the D linolyomide for the love and then the borteesib for the bones. NPNS is usually going to be polyythemia vera central thrombocythemia. And again what's really important to remember about these is that these are going to respond well. They can do well with a jack 2 inhibitor right they definitely can. But we actually see a better response initially and it's usually the better way to go about this is with something called cyto reduction. We prefer to give something called hydroxyhea. Do you guys remember hydroxyhea? That was one of those ribboucleide reductase. It was one of those anti- metabolites. So that's another one. But you also can give don't remember I mean don't forget you can also give roxalitin which is a jack 2 inhibitor. All right. Now another kind of group of malignancies is things like genital urinary ones like testicular cancer. Testicular cancer actually responds well to a combination 2:54:08 chemotherapy like the beep regimen which is usually going to be bleomy, a topocide and a platinum agent. So again you can see here is an anti-tumor antibiotic. Here is a topo isomease inhibitor, right? And this is usually going to be a type two. And then you have a platinum agent. This is an alkalating agent. So again, you're using combination chemotherapy here. Prostate cancer. This one is really targeting that androgen pathway. And so we like to give things that are going to target that. And so we use things like G&RH agonist, which is your loopy. That's going to lead to again a reduction in particular processes like production of FSH and LH. Again the importance with that is we didn't talk about this but LH is crucial for in the male testosterone production which can be converted into DHT and DHT can actually lead to the enlargement of a particular tumor. It's essentially an androgen. Um and so that's also crucial. So giving G&RH agonist like lupalide can inhibit that process and then giving anti-androgen receptors in worst case scenarios like enzolutamide that may be able to help these patients. Obviously the goal is a radical prostatctomy but this is in 2:55:04 combination. Renal cell carcinoma is one of those that a lot of the times it's usually performing some type of surgery. Um so usually this could be potentially depending upon the size of it you may be able to do a partial or maybe a radical nefrectomy but in metastatic cases we oftentimes have to reach for specific amunotherapies and that's where we actually like to dip into a combination of two amotherapies usually antiPD1 inhibitors and an anti-Cta4 inhibitor. All right, bladder cancer is actually interesting because again the goal here is depending upon if it's involving the muscle or if it's not involving the muscle. So usually intravvicicular mitoin C which is kind of one of those anti-tumor antibiotics can be used. You can actually indwell the bladder with this particular anti-neoplastic agent and it may be able to work against those cancers that haven't invaded the muscle of the bladder. But once it's kind of invaded the the muscle of the bladder, you may have to reach for more of the systemic kind of chemotherapy to really prevent the excessive metastasis. And that's when you get on to gym cytoine which is an anti metabolite and cyplatin 2:56:00 which is an alkalating agent. All right. Again you can remember this with the term great combo for the muscle invasive bladder cancer. Again gimcy and cis platin. All right. What about those scenarios of gynecological malignancy? So things like breast cancer. So in this scenario we like to really really consider serums as a beneficial drug. So this is usually going to be those that are working against those who are estrogen receptor positive and progesterone receptor positive and they're premenopausal. If they're post-menopausal, we prefer the aromatase inhibitors. If they have to add on CDK4 inhibitors, it's usually in combination with one of these two. So if a patient is for example stage 4 breast cancer and they have ERPR positive we could do a serum if they're premenopausal plus a CDK46 inhibitor or if they're postmenopausal aromatase inhibitor plus a CDK46 inhibitor right if they have triple negative breast cancer in other words they don't test for ER they don't test for PR and they don't test for her too that means that this is a patient who has triple negative breast cancer and they respond 2:57:00 well to doc rubicon which is what an anti-tumor antibiotic and pletaxyl which is a microtubial inhibitor You can remember no receptors. Okay, triple negative breast cancer because it has no positive receptors do pack attack. So doc rubicon and pletaxel anti-PD1 inhibitors are really kind of one of these niche ones that we can add on. Again, this is pimberly, but usually we have to look at what's called the PDL1 expression. So this is getting into more of particular pathology and imuninohistochemistry testing to see if they have a positive PDL1 expression that's usually greater than 50%. And if they do, they will respond well to inhibiting that PDL1 PD-1 interaction with pimberlymath. All right. Ovarian cancer. Ovarian cancer also is one of those that responds, especially since it's a solid organ tumor. Usually responds well with in these scenarios some type ofctomy. Sometimes it may be involving and certain scenarios you may have to remove the uh ovary and parts of the fallopian tubes. In some worst case scenarios, you may even have to remove the uterus. And so sometimes a lot of 2:58:02 you know we we see it a lot uh ovarian cancer is a total abdominal hysterctomy with a bilateral sopingoctomy and that's usually the standard but sometimes if it is really really severe and it's already metastatic which is what happens a lot of the times unfortunately with ovarian cancer it's usually doing the best thing you can to do the total abdominal hyome hyerectomy the bilateralctomy debulking and then adding on chemotherapy like carboplatin pletaxel and again you can see this is a platinum agent and this right here is But that is going to be a microtubial inhibitor. All right. The next thing is indications of chemotherapy agents for small cell lung cancer. Any kind of respiratory malignancy. So small cell lung cancer is very very very aggressive. Usually by the time it's diagnosed it's extremely extensive. The goal here is to remember by that time you're treating them with chemotherapy. They're not going to respond well to any kind of surgical procedures like a lctomy, pneuminctomy, radiation therapy. At this point you're probably more likely doing chemo and then maybe doing cranuli radiation therapy sometimes or prophylactically at least. And so the agents that you'll 2:59:00 probably most likely use is cis platin which is a platinum agent and autotoposide which is a topo isomease inhibitor usually a type two. All right you can remember this by the term elementary cells. So e attoposide and cis platin is going to be great for small cell lung cancer. For non small cell lung cancer, these are really kind of you oftentimes, for example, in these chemotherapy is usually going to be the backbone in combination with determining if you can do things like a lobectomy, if you can do things like a pneuminctomy, if it's maybe areas that you can do like a stereotactic ablation. Um, a lot of the times that's the goal is to do some type of surgical procedure, but as it starts to get more advanced, then you need to add on things like radiation therapy and sometimes chemotherapy. And usually the the base or core of this is cy platin, pimitrexid, and gyctoine. Again, platinum agent. And again here, this is a an anti metabolite. We didn't talk about pimatrix, but again, these are usually your core. And then what I think is important is as that core sometimes 3:00:00 if the patient has specific mutations that are present we may add on other things like I talked about the al rearrangement kind of mutation we can add on things like for example for that one electip if they have the eGFR mutation we can do things like if they have PDL1 expression that's greater than or equal to 50% we can do like an anti-PD1 inhibitor like a pembrlymab and so those are other things that we add on but again I want you to remember the non small lung lung cancer by cough, puff or gasp. So cis platin, pimittrixad or gyctoine. So we can use that in non small cell lung cancer. Again this is just paying homage that you can add egfr inhibitors if they have the mutation. So if they have the mutation oertinib if they have this mutation elective and if they have some type of pdl1 expression that's greater than equal to 50% you can do an antip-d1 inhibitor. So that's the whole thing of kind of depending upon the underlying clinical scenario you're usually using multiple modalities. It's not just chemo by itself. A lot of the times it's often in combination with surgical intervention um radiation 3:01:02 therapy that may be used adgiuantly sometimes neoagivantly and then chemotherapy agents they can be used adgivantly or neoagivantly which again mean that either neo it's before kind of a procedure or adgivantly after a particular procedure and so that's something to remember here. Now what about neurological malignancies? Again the big one is a GBM. A lot of the particular neurologic malignancies we don't use chemotherapeutic agents. It's most often it's surgical intervention uh is the best way or treating the associated complications of that tumor. With GBM, it's one of those again you do the best that you can to attack this surgically, but oftent times there isn't much that you can do because of how extensive it is um and because of the aggressive nature. But sometimes we will attack this with a combination of neurosurgical intervention and teosolomide which is a type of alkalating agent. All right. For skin malignancies like melanoma, the best practice is a wide like local excision. So doing a surgical excision getting really good margins is the best way to 3:02:02 go. But on top of that because melanoma is extremely aggressive and metastatic you may need to then say okay because there is this metastatic melanoma I may need to use chemotherapy agents because again the surgical excision will take care of that problem but at the point of where they have systemic metastasis you need a chemotherapeutic agent and usually graph mech inhibitors are going to be beneficial but I would say these are more beneficial if you have a specific mutation because as we talked in skin cancer we know that patients have specific breath mutation that puts them at high risk and if we can give them vimaraphanib it'll attack those people who have these what's called V600DE mutations but often times more than not antiPD1 inhibitors would probably be the way to go for any metastatic melanoma and then you can consider the something like a graph or mech inhibitor as an alternative if they have the V600E mutation. What about bone and soft tissue malignancies? We didn't talk about these in oncology. We'll talk about this more in pediatrics but pediatric um osteocarcomomas 3:03:03 again we're going to potentially use these with certain types of therapy uh but I think a lot of the times we'll kind of use chemotherapy like methtoate which is an anti metabolite doc rubicon which is again what type of agent this is usually an anti-tumor antibiotic and then cy platin which is an alkalating agent and then ooing saroma this one can be used with a cycle of encristine doc rubicon cyclophosamide and then you follow it up with a cycle of iosomide and a topic so multiple multiple different agents. All right, with gastrointestinal malignancies we think about colurectal cancer. So what are some chemotherapy agents we use here? Full fox is a common one. Again, colorectal cancer. Sometimes we'll be doing things like hemiclecttoies, partial callectomtoies, total callectomies. You may need to do particularly like some radiation therapy. A lot of the times you may need to do chemo. In certain situations you can even use amunotherapy. Um but in this scenario I think one of the common chemotherrapeutic regimens that are involved is the full fox regimen. So full fox is full is luccoin which is a folinic acid. Uh F5FU which is the 3:04:04 floruricil and then ox is oxyoplatin. So luccoorin is basically going to enhance the activity of fifloruricil and oxyoplatin is going to be one of those alkalating agents is the platinum compounds. Another option is fulfury. So fulfury is again luccoin which is the folinic acid. Five florauricil which again luccoin is just going to help to enhance the activity of five floruricil and then irrein which is this is a type one topo isomease inhibitor another thing that you can give again depending upon if the patient has specific mutations is the bevicismab which is the veg f kind of inhibitor remember it's the monoconal antibbody and so it's going to reduce that angiogenic process and starve the actual cancer cell that's usually if they don't have a specific type of kraz or bf mutation they're more of that wild type. Satuxmab is going to be one that you actually give, which is a monoconal antibbody that again actually helps to work specifically at that receptor um which is one of those EGFR receptors 3:05:05 that then helps to stimulate the pathway of developing uh the RAZ and the RAF pathway. And so if that mutation is present, giving something like satuxmab might actually be able to help. And so that's something that you would consider. AntiPD1 inhibitors is really if they have something more like Lynch syndrome. So if they have more of that MMR or that microatellite instability that's present an antiPD1 inhibitor like pembrlymap may be beneficial but I really want you to focus on that fulfury and then consider these dependent upon those clinical scenarios. All right, then pancreatic cancer. Again, we're going to use something called fulfirinox. And again, it's not too bad. Again, we already know that the fo is lucorm, which enhances the activity of 5FU. And then we know that we're going to have irreoticin, which is a topoase type one inhibitor. And then we're going to have oxaloplatin, which is an alkalating again platinum agent, and that's going to be really good for pancreatic cancer. Again, pancreatic cancer, a lot of the times we may have to involve a surgical intervention as well, depending upon if it's usually more near the head, which is usually 3:05:58 what often happens, you need to do some type of a whipple procedure. And if it's usually near the tail, you may have to just do a tail end resection. and sometimes remove the spleen as well if it's kind of close in that area. But again, it's usually dependent upon this. It's combination with the chemotherapy. And we already know that this cancer can be very very aggressive. But I hope that with that this makes sense. So now what I want to do is I want to step over into the realm of again I'm giving all of these different agents to individuals, but I want to make sure that I'm not causing any kind of toxicity. I'm not causing any kind of like terrible adverse effects, which is going to happen no matter what. But how do I know which agents come with particular adverse effects? And then how do I monitor it? And is there any way in certain types of toxicities, how I address them? How do I reverse them? How do I kind of consider these things ahead of time? Let's actually do that now. All right, my friends. We're almost done. At this point, we've decided we have a patient who's suffering from an unfortunate cancer. We start them on chemotherapy. Maybe it's a combination chemotherapy. 3:06:57 And one of the things that we want to be able to do is watch out for any adverse effects. Sometimes you can monitor for these things. And it's really ideal to know that because that could be a question on your exam is, hey, you put a patient on this particular medication. What should you be monitoring them with? And that could be a way of kind of monitoring for the complication that they could have. Right? So, we're going to use this chemo man, which is a common one that you see in all the different textbooks, the first aid, AMB boss, you know, UWorld, it's all over the place and it's well known. And so, we're just going to kind of expand on it just a tad. All right. So, let's say for example, we take chemo man here and we talk about the ears. Well, we're going to do this in the shape of what looks like a C, right? And so there's different drugs like cis platin. So cis platin is definitely one. Um, and then the other one, it's it's kind of its cousin is caroplatin, but I'd say cis platin is probably going to be the more powerful one here. It can really damage the inner ear. And so it can lead to ototoxicity. So you could things develop things like sensory neural deafness. And 3:07:55 so that's one thing to definitely consider is oto toxicity. Now how would you monitor that right I mean there is there a way absolutely hearing testing right so you can definitely do sensory neural testing and if you have any confusion of like hey I don't know if it's conductive deafness or sensory neural deafness you can do the Weber Renee test from there determine hey they need sensory neural testing to see do they have any sensory neural deafness right so that's one thing to consider there um the next thing that I would say is let's move from here and let's move down and let's go and draw this we're going to draw the lungs and they're going to look like a bee and this is called bleom me. So this is called bleomy. Now bleomy can lead to something called pulmonary pulmonary fibrosis. So this can lead to something called pulmonary fibrosis. So pulmonary fibrosis is basically kind of it can generate what's called a restrictive lung disease. And so if you have fibrosis of the lungs, you restrict the expansion of the lungs and this can lead to some problems with that. Right now, 3:08:56 what would be something that I would want to monitor for a restrictive lung disease? How could I potentially monitor that? I'd say PFTS would be a pretty good start, right? So, that's something to definitely consider is maybe monitor the patient's PFTs. Keep an eye, make sure that they're not kind of moving into that kind of restrictive lung disease type of pattern. So, PFTS, DLCO, things of that nature could be potentially beneficial to be checking. All right, so just keep an eye on that. Um, what's the next one? All right, let's move on to the next one. Let's draw something that looks like a heart, but we're going to do that in the shape of a D. And then we're going to draw a T in there. All right. So, this is going to be doc rubicon. So, do rubonin. And another one is tresstuzumab. Tstuzuab. And again, I think it's always good to remember these are alkalating agents, anti-tumor antibiotics. Anti-tumor antibiotic, monoconal antibbody. What will this do? This is going to act on the heart. Boo- boo. And so because of that, this can lead to cardiotoxicity. 3:09:56 If it leads to cardiotoxicity, what kind of cardiotoxicity are we talking about? It's usually dilated cardiammyopathy. So that's really the way that you'd want to consider it is is is it can lead to something like dilated cardiomyopathy, which you'd have to get an echo. You'd have to be checking some type of like echo process to think about this one. So again, uh cardio, let's actually fix this one right here. This is cardio toxicity. All right. So you'd want to be checking a echoc cardiogram because echo cardiograms are generally beneficial in the sense that we can say hey what's the left ventricle doing? Do they have any evidence of like a bis bentricular di systolic like enlargement? Is there a weak or very reduced ejection fraction? And so that's something to definitely be looking for is looking for bentricular enlargement looking for a decreased um ejection fraction evidence of any kind of systolic heart failure. All right. The next thing is, so we have this part here. Let's move into the kidneys. And the kidneys, we're going to do this green. They look like kind of C-shaped. 3:10:59 And it's the same group up here. So this could be cis platin, right? So this could be like your cis platin. And cis platin can lead to something called nephrotoxicity. So nephro toxicity. And with nephrotoxicity, we worry about kind of a rising creatinine level, right? Or maybe a potentially an acute kidney injury. And so what we'd want to be doing for this one is monitoring the patient's renal function test. I definitely be checking things like their renal function test, whether that be like a BMP, a CMP, or a specialized renal function panel. Either way, check that renal function. All right? You want to make sure that they're not having any rising creatine or decrease in their GFR, particularly the more the bump in the creatinine because of the risk of AKIS. All right, the next one. Let's do this one in orange given the bladder. And we'll draw this. What? It's a C. And then we'll draw like a Y kind of like into the urethra portion there. That's going to be cyclophosphomide. So cycllo phosphomide. This one 3:12:00 is pretty nasty to the bladder. It can lead to something called hemorrhagic cyitis. So this can lead to hemorrhagic cyitis and in some cases it can increase the risk of bladder cancer. All right. So hemorrhagic cyitis definitely something to think about here with cyclophosphomide if it does potentially increase the risk of this condition. How would we monitor that? Well, obviously it's asking the patient if they have any changes in their urinary patterns, but I think sometimes it's always beneficial to maybe check a ur analysis and always follow that up with a microscopy because just because you have hematia doesn't mean it can't be something else uh due to like an infection, due to things like glamular diseases even though it's extremely rare, kidney stones. So, always check that uralysis with a micro um to really take a look and make sure that it's truly like gross hematia and it's actually real. It's not pseudo hemateria. All right. So, that's that part. Now, the next one here is we can 3:13:01 kind of draw these. Let's actually kind of do this interestingly here. You see how the arms they kind of look like a V? That's a reason for that. And this V is for the vinka alkyoids. All right. So, you have things like vinristine and you have what's called vinlastine. So and vinlastine and these can actually damage the nerves your peripheral nerves and they can lead to something called peripheral neuropathy. Now peripheral neuropathy obviously when we talk about this one it it you know you're talking about potentially like loss of sensation. So decrease pain, temperature sensation, vibration sense, uh proprio reception and so they can even have pain like paristhesas as well. And so these are definitely things to be thinking about. And often times it's just really important if the patient's on this to be asking them about that, 3:14:03 but also be doing a very thorough neuroexam doing your monofilament test. Do getting out your tuning fork, banging that thing and checking to see if they have vibration sense. Checking their finger position. Hey, where's my finger? Up, down, up, down. Proprioceptive sensation. checking for fine discriminative touch. So, making sure that you're doing a very good neuroexam is going to be important to identify any of these things. All right. And then, son of a gun. The next one that I want you guys to understand here is a little bit of a stretch, but it's it it works. And this one is going to be kind of representing the bone. So what I want you to do is we're going to draw a five six a line and then an MTX. Five six lines MTX. This is kind of trying to represent the femur in a way. And so this is going to be five is five FU. Six is six mercaptoine and MTX is methate. 3:15:08 These act on the bone marrow. When they act on the bone marrow, so we'll represent it like this, it can lead to something called miloppression. Milo suppression. So myoppression is you can potentially drop your cell lines. What kind of cells? Well, the myoid stem cell lines. So your white blood cells, your red blood cells, your platelets, they could all potentially drop, dude. And so what should you be watching for? I'd check a CBC to keep an eye on these patients. Right now, there is other adverse effects that you guys definitely should be aware of. I mean, just because I'm mentioning these doesn't mean that there's other drugs that don't share some of these. And and and for I'll give you an example. So, so for example, you know, we can also say that drugs like um methtoate can cause nephrotoxicity. That's a pretty common one. Um I could even say that things like your taxes which are also microtubial inhibitors things like your dosataxel palletaxel that can cause 3:16:08 peripheral neuropathy. Um oxaloplatin which is a type of which is a type of um one of those platinum compounds of the alkalating agents. It can actually cause cold induced neuropathy. So many of these drugs honestly almost all of these drugs can cause any drug can cause miloppression. These just tend to cause the most severe miloppression. I mean, methtores can cause hepatitis. I mean, the list goes on. These are just the ones that you're most likely to get tested on is what I want you guys to think about. Now, what I also want you guys to remember is when we talk about these drugs, there is this other category called immune checkpoint inhibitors. And this is something that um it's really important. I used to see a lot in ICU when you give immune checkpoint inhibitors is patients would develop some issues where when you give these yeah you're giving it to target this types of reactions here. However, it's not uncommon for sometimes these monoconal antibodies to attack other tissues and if it attacks these particular tissues they could develop 3:17:09 unfortunate kind of like itises right the itis effect. So for example, if it attacks here, you could get something like colitis, you could get pneumonitis, you can get thyroiditis, you can get hepatitis. And so that's important to remember. So what could we see here? You could see things like colitis. What would that look like? I mean it can vary. Obviously it could be abdominal pain, maybe a low-grade fever, diarrhea. Here you could have pneumonitis. This could be potentially this could this could range. I mean, this could start off with just like shortness of breath and it could completely go full-blown into things like cough, bronco spasm, hypoxia. This could be thyroiditis and this could literally cause transient hyperthyroid symptoms. So, they could have abnormal, they could have a high thyroid hormone, right? And so, that's another one to be able to think about here. Uh, which would they kind of present with like, you know, with this one, it would have a transient effect. It's not going to be long term. Uh and then the next thing is well if you actually do continue to cause these um if these maps continue to damage the actual thyroid tissue it can 3:18:08 go from a transient hypothyroidism to a permanent hypothyroidism. But either way we'll talk about that on another day. And then damaging the liver you could have hepatitis. And that's why it's actually very crucial when you put a patient on immune checkpoint inhibitor to be doing things like checking their pulmonary function, checking a thyroid function panel, checking their LFTs. These are super super crucial. All right, that really gives you the adverse effects. And when we talk about adverse effects, there's always some way or shape or form that they try to kind of maybe squeezle this into the exam sometimes. The real thing when it comes to detoxifying agents, I don't think for a lot of these that you'll get tested on them. I think that there's probably one, and that's going to be methtoresate. They may ask this question and there's two reasons why and I'll talk about it. Could you possibly um be asked a question about other ones? Yeah, you know, sometimes you could see things maybe cycllo 3:19:11 phosphomide. Um I I'd say that's a it's it's less likely, but methtoresate if a patient came in with things like severe hepatitis, miloppression, you should know what to give them. If they come in with hemorrhagic cyitis, you should know what to give them. Um, cy platin, I do think that this is something to consider. Oftentimes it unfortunately leads to dialysis, but we should talk about this, especially if it's really bad enough nephrotoxicity. And then the last one is doc rubicon. So if you're kind of in that cardiology area, this may come up as well. But when we talk about these the thing to think about here is whenever a patient gets methtores and let's say that they develop a you know some type of complication myoppression is is one to think about here if they do or hepatitis we can potentially reverse that or kind of rescue the methtoresate effect with a drug called luccovorin. All right so that's one to think about. Let me explain what I'm talking about here. All right remember this pathway that we talked about seven years ago at this point um it's coming back. So if you 3:20:11 guys remember we have something called folate right and then folate gets converted into dihydroofolate that gets converted into tetrahydropholate that gets converted into 510 methylene I'm just going to put me for right now tetrahydroofolate this was that pathway that we talked about and folate when it goes this way there's a couple enzymes involved right this enzyme here is really important and this is called which one dihydropholate reductase that's the one that this guy inhibits. There's also this one called thyolate synthace. What does he do? This is a good recap, right? He helps by taking things like your deoxyurodine monofosphate and converting it into deoxyodine monofh phosphate which we can incorporate into the DNA. And so whenever I use this that helps to drive that process. Yeah. Well, guess which drug inhibits this one? 5FU. So 5FU works here and methtoresate 3:21:14 works here. So what these do is these drugs actually work to inhibit these enzymes. So whenever we do that, what we know is we because we've already talked about this, we don't know need to go crazy. It basically shuts down this pathway, shuts down the formation of DTMP and shuts down the DNA. Right? If a patient's on methtoresin, we shut it down too much and we shut down that DNA synthesis enough that we're causing um milo suppression, we can give luccoorin. The concept behind lucorin is that luccoorin is like a form of tetrahydroofolate. And so essentially what you're going to be doing is you're bypassing. So you're bypassing the enzyme. That's all you're doing. You're bypassing the enzyme. And so you're basically rescuing the patient. You're giving them this form of tetrahydropholate and then that's going to allow for them to go this way. It'll push them in this direction so that you can make more of this so that you can stimulate this reaction. Increase more of this increase. You see what I'm saying? That's kind of cool. And so 3:22:14 that's the rescue process. So lucavin will help to rescue methtoresate. However, if you give luccoorin, it actually potentiates the effect or enhances the effect of 5FU. So that's what sometimes they'll try to test you on is if you give lucavorin what would it do to methtoresate and what would it do to the 5FU it'll rescue right the methtoate and enhance the 5FU that's what I want you guys to remember all right these other ones cyclophosphomide we can give particular agents doc rubicon we can give particular agents so if you really wanted to remember the cyclophosphomide you can give something like mezna Uh, and you can I'd really focus on the fluids. Cyis platin you can give things like ammystine but I'd really focus on the fluids and the potential need for diialysis. And then docar rubicon we can give something like dex rzoxone dexra zoxane actually dexane. 3:23:15 All right. So these are things that you can consider but the really important one that I want you to remember is the lucco. All right. So this really man I mean we we talked about a lot in this lecture. We talked about the cell cycle, the cell cycle regulation, the immune processes, the angioenesis. We went through the cell cycle specific, the cell cycle non-specific anti-neoplastic agents. We went through the drugs that influence protein kinases. We went through drugs that influence the hormonal mechanisms. We went through drugs that influence the monoconal antibodies. We went through drugs that influence the immune checkpoint. We talked about it in a holistic view. We talked about what are the combinations that are commonly utilized in different types of cancers and then we finish it up with what are the primary adverse effects that you could be tested on how to monitor them and then the last thing is we finish off with what's a rescue med that we should know especially in methtoraate toxicity my friends I really hope that you like this lecture I hope that you learned a lot if you did 3:24:16 support us hit the like button comment down in the comment section subscribe but my friends I love you thank you and as always until next Bye.
