0:00 Cancer treatment is divided into four main types - surgical, radiation therapy, 0:11 chemotherapy, 0:12 and biologic therapy. 0:14 Now the goal of cancer treatment is to eradicate the cancer. 0:18 Every cancer treatment has the potential to cause harm, and treatment may be 0:22 given that 0:23 produces toxicity with really no benefit. 0:26 In this video we're going to talk about chemotherapy agents and their mechanism 0:29 of action. 0:31 Chemotherapy agents have different mechanisms of action and target different 0:35 parts of the 0:36 cell cycle. 0:38 Combinations of these chemotherapy agents are preferred because different 0:42 mechanisms of 0:43 action means that they work on different parts of the cell cycle, which means 0:48 that overall 0:50 less side effects. 0:53 In order to understand how chemotherapy drugs, chemotherapy agents work, we 0:57 firstly have 0:58 to revise the cell cycle. 1:01 The cell cycle has four phases. 1:04 The growth one phase, or the G one phase, where the organelles duplicate. 1:09 The S phase, which is where the DNA basically replication occurs. 1:14 The growth two phase is when the cell prepares itself for the M phase, which is 1:21 mitosis, 1:21 where the cell divides it to two identical daughter cells. 1:26 Then the cell cycle will repeat itself. 1:31 We can further explore mitosis. 1:33 Mitosis has other phases. 1:36 The pro phase is where the centrosome duplicates and form these microtubules. 1:42 In metaphase, the chromosomes, the DNA really, align in the middle of the cell, 1:47 and the microtubules 1:49 that were formed from the centrosome attach to the centromeres, which are the 1:55 center points 1:56 of the chromosomes. 1:58 In anaphase, the chromosomes are separated and reach either end of the cell. 2:07 In cellophase, the cell membrane constricts ready to separate and then a new 2:12 nuclear membrane 2:14 is being formed. 2:17 The cell cycle is a continuous process, and so you have checkpoints during the 2:22 cell cycle 2:23 to make sure that there are no abnormalities in the cell before it progresses 2:28 to each phase. 2:30 These checkpoints include the G one checkpoint, the G two checkpoint, and the M 2:36 phase checkpoint. 2:37 One thing these checkpoints look at is whether there are abnormalities, damage 2:42 or mutations 2:43 to the DNA, for example. 2:45 DNA is a double helix structure composed of four nucleotides. 2:51 After the G one phase, where the organelles duplicate, comes the S phase. 2:58 In the S phase, DNA becomes replicated. 3:02 Let's revise this process. 3:04 During replication, the DNA strand is separated by an enzyme called helicase. 3:10 During the unwinding of DNA, tension can occur distally. 3:15 The tensions are these coils that are being formed. 3:19 The cells have a normal biological mechanism to fix these coils and super coils 3:25 that are 3:26 being formed. 3:27 This mechanism is an enzyme called topo isomerase. 3:32 Here topo isomerase two fixes these super coils, reducing the tension in the 3:39 DNA strand. 3:40 And we'll talk about topo isomerase later on. 3:44 Now, there are four types of nucleotides as mentioned in DNA. 3:49 These nucleotides can be divided into two groups, pyrimidines and purines. 3:56 Pyrimidines include thiamine and cytosine, and purines include adenine and guin 4:01 ine. 4:01 So what happens is a double strain of DNA gets unwind by helicase into two 4:05 separate strips. 4:08 Another enzyme called DNA polymerase will create a new strand on both strips. 4:13 The new strand following the helicase is the leading strand. 4:19 The lagging strand is the strand that is created in segments. 4:30 Chemotherapy agents target different parts of the cell cycle, as mentioned. 4:36 Because of this, they are grouped into different classes. 4:39 Let's take a look at the different classes, one at a time. 4:43 First, let's begin with alkylating agents. 4:46 The oldest anti-cancer cytotoxics. 4:48 Now, these agents are anti-proliferative drugs. 4:52 They work by binding covalently via alkyl groups to DNA. 4:57 They then form cross links and thought to arrest the cell cycle in the G1 or 5:03 the S-phase 5:03 of the cell cycle. 5:05 Now the alkylating agents actually bind to the nucleotide guinine. 5:10 Once bound, they form cross-linkage of DNA strands. 5:14 Broken or cross-linked DNA is intrinsically unable to complete normal 5:20 replication or 5:22 cell division so they undergo cell arrest. 5:25 They stop. 5:27 Because they are in cell arrest, the cell will then either be repaired, so it 5:33 can proceed, 5:34 or progress through the cell cycle, or the cell will undergo apoptosis, 5:40 basically dying. 5:42 Examples of drugs in the class of alkylating agents include nitrogen mustons 5:47 such as cyclophosphamide. 5:49 And there's also cisplatin. 5:51 Now, cisplatin is an interesting drug. 5:55 It is one of the most active anti-cancer drugs and used on many types of 5:59 cancers, but 6:00 also come with many toxicities. 6:03 It is actually its own class, but has similar mechanism of action to alkylating 6:08 agents, 6:09 and so it is put in this category. 6:12 The next class of chemotherapy agents are the anti-metabolites, or the anti-met 6:17 abolites. 6:18 These guys interfere with normal cell metabolism of nucleic acids, so really 6:23 they disrupt DNA, 6:25 RNA metabolism production, interrupting the S-phase of the cell cycle. 6:30 You will focus on DNA metabolism here. 6:34 And the four nucleotides for DNA are thymine, cytosine, adenine, and guanine, 6:38 of which thymine 6:40 is strictly DNA. 6:43 Thymine, the DNA nucleotide, is made after a series of reactions. 6:47 One important reaction is from dUMP to dTMP. 6:55 This reaction is carried out by an enzyme called thymidylate synthase. 7:00 For dUMP to convert to dTMP requires a co-current reaction, which thymidylate 7:08 synthase also 7:10 carries out. 7:11 This is the conversion between methylene tetrahydrofolate to dihydrofolate. 7:19 So thymidylate synthase catalyzes methylene tetrahydrofolate and dUMP to form 7:26 dihydrofolate 7:28 and dTMP, dihydrofolate is converted to tetrahydrofolate. 7:34 By another important enzyme, dihydrofolate reductase. 7:41 Tetrahydrofolate becomes methyl tetrahydrofolate once again. 7:47 So this whole reaction involving these two enzymes, thymidylate synthase and di 7:51 hydrofolate 7:52 reductase is important in order to make DNA. 7:56 By interrupting any of these two enzymes, you are essentially disrupting thym 8:01 ine, thymidine 8:02 synthesis, and thus DNA synthesis. 8:08 A few chemotherapy agents work here. 8:11 These include five floral uracil, which inhibits thymidylate synthase and also 8:17 specific thymid 8:18 ylate synthase inhibitors. 8:20 A very common drug used in rheumatoid arthritis also is a chemotherapy drug and 8:25 an ectopic 8:26 pregnancy drug. 8:28 This drug is methotrexate and it works by inhibiting dihydrofolate reductase. 8:34 Other chemotherapy agents that work specifically on disrupting purine 8:39 metabolism and synthesis 8:40 include rheumatoid and theoguinine here. 8:45 In summary, anti-metabulites work by disrupting DNA RNA metabolism and 8:53 production and thus 8:55 it will disrupt cancer cells from progressing through the cell cycle. 9:01 The next class are anti-tumor antibiotics. 9:06 Main ones include a group called antarcyclines. 9:10 These antibiotics have several mechanism of action, but their specific 9:14 mechanism of action 9:16 is unclear. 9:20 One effect is that these anti-tumor antibiotics inhibits topoisomerase 2. 9:26 Remember, topoisomerase are important enzymes in maintaining the structure, the 9:30 topology 9:31 of DNA. 9:33 Topoisomerase 2, relaxes supercoils by breaking two DNA strands, unwinding it, 9:39 relaxing it, 9:40 and then attaching it back together once it's unwound. 9:45 And so by inhibiting topoisomerase, DNA doesn't relax and so replication 9:49 becomes hard with 9:50 the supercoils, or maybe the topoisomerase breaks the DNA strand but then can't 9:56 really 9:56 attach it back together, either way DNA replication is inhibited and the cell 10:01 doesn't progress 10:02 through the cell cycle. 10:05 Another way antibiotics work is by inhibiting helicase, the enzyme which unwind 10:10 s the DNA. 10:11 By inhibiting this enzyme, you inhibit DNA replication. 10:15 Finally, antibiotics such as antarcyclines induce reactive oxygen species 10:19 formation, 10:20 causing destruction of the cell, and triggering apoptosis. 10:26 Examples of antarcyclines include doxerubicin and donorubicin. 10:33 The next class of chemotherapy drugs are the topoisomerase inhibitors. 10:38 Topoisomerase, remember, are essential enzymes in regulating the topology of 10:43 DNA helix. 10:44 There are two types of topoisomerase. 10:47 There's topoisomerase 1 and there's topoisomerase 2, which we have already 10:51 talked about. 10:53 Topoisomerase 1 cleaves only one strand of the DNA and relaxes DNA coil during 11:01 replication. 11:03 Topois here is a DNA double helix. 11:05 The topoisomerase 1 will click one strand and then unwind it and attach it 11:15 causing one 11:16 less coil. 11:19 Topoisomerase 2, as mentioned, cleaves two strands of the DNA helix and relaxes 11:25 super 11:25 coils during DNA replication, which, again, we've already talked about. 11:31 Topoisomerase 1 inhibitors inhibit topoisomerase 1, and thus inhibits the 11:38 relaxation of DNA 11:40 and thus potentially inhibits proper DNA replication. 11:45 Example of this chemotherapy agent is Camtothecin. 11:51 Topoisomerase 2 inhibitors we already talked about and include etoposide. 12:01 The next chemotherapy class work on the M phase of the cell cycle and are 12:11 called the 12:11 anti-microtubule agents. 12:14 These guys disrupt the M phase of the cell cycle, leading to cell arrest, which 12:19 then will 12:20 lead to apoptosis. 12:22 These are the taxanes and the vincter alkaloids. 12:26 Let's just quickly recap the M phase to understand how these anti-microtubule 12:32 agents work. 12:34 The M phase consists of the prophase, metaphase, anaphase, and chilophage. 12:40 During early mitosis, microtubules are extending from the centrosomes and 12:46 attached to the centromeres 12:47 of the chromosome. 12:49 The microtubules allow for the separation of duplicated DNA into either side of 12:56 the cell 12:57 before the microtubules start degrading and breaking down. 13:02 Vinca alkaloids inhibit microtubule assembly or formation, and so are known as 13:10 microtubule 13:12 destabilizers, without no microtubules forming, this will disrupt the M phase 13:18 causing cell 13:19 arrest. 13:25 The other group of anti-microtubules are the taxanes. 13:29 These guys bind to and stabilize the microtubules that are already formed in 13:34 the M phase and 13:35 so these guys are called the microtubule stabilizers. 13:41 They basically inhibit the breakdown of the microtubules once they are formed 13:45 and so you 13:46 don't complete the M phase of the cell cycle, which means you get M phase 13:50 arrest, you get 13:52 cell arrest. 13:53 The other important class of chemotherapy agents are the hormonal agents, which 13:58 are not discussed 13:59 here because there are many types, hopefully a separate video will look into 14:04 this. 14:04 Thank you for watching, I hope this helped. 14:08 Thank you for watching, finally it's very important to understand the side 14:11 effects of 14:12 chemotherapy agents. 14:14 I have a separate video on that which looks at the side effects, the acute side 14:17 effects 14:18 of chemotherapy agents, thank you for watching.
