 To understand the mechanism of action of antineuplastic drugs, it is very important to first understand certain aspects of cell cycle. So we will deal with anticancer drugs and the cell cycle together. So first class of anticancer drugs is alkylating agents. These drugs act on G1 phase. They bind to guany nucleotide in DNA strand and this causes cross-linking of DNA strand. So they are binding on this guanine and this guanine and they will interlink. This basically is causing DNA damage. Hence this damage is detected by our surveillance mechanisms which will halt the cell cycle by activating P53. P53 activates P16 which in turn inhibits CDK. So CDK activation cannot occur. So if this is not getting activated, obviously the cell will not progress to the next stage. Now there are certain cancer cells with P53 mutation. So cancer cells with P53 mutation are resistant to these alkylating agents. Well now another drug Cysplastin also acts just like these alkylating agents. Now next class of drugs acts in S phase that is DNA synthesis phase. So first we should know important requirements for DNA synthesis. First of all DNA synthesis requires that DNA strand should separate properly. This is done by helicase enzyme and synthesis of new strand should occur which is done by the enzyme polymerase. Now during this separation of DNA strands, supercoils accumulate in the rear end of DNA. Something like this. See this is a coil thread and if I open this coil thread from one side, the other side is getting strained and supercoils like this are accumulating on the other end. So this will form knots. Similar thing happens in DNA. For DNA synthesis to take place continuously these supercoils need to be removed. This is done by the enzyme DNA topoisomerase. Now this DNA topoisomerase are of two types. Type 1 and type 2. Type 1 cleaves only one strand of DNA and relaxes DNA coils. While type 2 breaks both the strands, then it unwinds them and then receives them. This is important for replication, repair as well as transcription. Then finally the third requirement is that a nucleotide substrate should be available for DNA synthesis. So these include purines that is z-9 and guenine and pyrimidine that is cytosine and thymidine. So there are drugs which act here and here. The drugs which act here are topoisomerase inhibitors which are of two types. Topoisomerase 1 inhibitors and topoisomerase 2 inhibitors. Topoisomerase 1 inhibitors are camptothicin analogues. So with their inhibition what happens is they can still cleave the DNA but the resealing of the strand is prevented. So this introduces single-stranded breaks in DNA. Now single-stranded breaks as such they are not lethal but see synthesis of DNA is taking place. So when the progressing replication fork meets the broken area, new DNA will not be synthesized since here there is a break. This will cause irreversible double-stranded DNA break. So they act on S phase. But the cells get arrested in G2 phase since transcription is not possible across this breaks in DNA strands. Then there are topoisomerase 2 inhibitors. These are epipodopylotoxins. Example is etopocyte which act just like topoisomerase 1 inhibitor such that breaks in DNA occur but they are not resealed. So cells are arrested in G2 phase. Okay, let's move to next class of anti-cancer drugs which act here. Now the DNA substrates which we talked about that is the purines and pyrimidines. They are denovo-synthesized in the body, the ones which enter through food are not even absorbed. Then these base analog of purines and pyrimidines are converted to nucleosides and the nucleosides are further converted to nucleotides. And these nucleotides actually get incorporated into DNA and RNA. So these are the building blocks of DNA and RNA. So the anti-cancer class of drugs which act on this phase either interfere with the synthesis of purines and pyrimidines or the incorporation into DNA or may be by both these mechanisms. These are known as anti-metabolites. During the synthesis of purines and pyrimidines there is a very important reaction in which D-UMP is converted to D-TMP by the enzyme chymidylate synthase. In this reaction, methylene tetrahydrofolate transfers a methyl group and is itself converted to dihydrofolate. Now this reaction to occur again, dihydrofolate should be converted back to tetrahydrofolate by the enzyme dihydrofolate reductase. So that tetrahydrofolate is available again for transferring the methyl group. So there are drugs which block this enzyme dihydrofolate reductase known as folate antagonist. Example is methotrexate. So if this enzyme is blocked, the synthesis of D-TMP cannot occur further. Then there are purine and pyrimidine antagonists which are either the purine or pyrimidine base analogues or nucleoside or nucleotide analogues. Examples of these base analogues include a six mercaptopurine and a six thioguanine. These inhibit critical steps in the synthesis of purines. Then there is phytofluorouracil which inhibits thymidylate synthase. Again a step in synthesis of bases. Nucleoside analogues are analogues of adenine and cytosine that is a cytosine arabinozide and gemcitabine. Since the base analogues of adenine and cytosine can't be taken up by cells, only nucleoside analogues are taken up by cells and converted to nucleotides. So we use their nucleoside analogues. Then example of nucleotide analogues is pudaramine. This is converted to nucleoside in plasma and is then taken up by cells. These analogues get competitively incorporated into DNA and form dysfunctional DNA. They also inhibit the enzyme DNA polymerase so the synthesis of new DNA strand doesn't take place. Then another class of drugs which act in this phase are antibiotics. All the drugs in this class intercalate between DNA strands and interfere with replication. Exact mechanism differs from antibiotic to antibiotic which we are not going in detail and many of the actions are not even known. Some example of the drugs in this class are actinomycin D, anthracycline D, donorubicin, doxorubicin, bluomycin. Okay, now let's come to drugs which act on mitosis phase. Mitosis consists of four phases, prophase, metaphase, naphase and telophase. In prophase condensation of chromosome occurs. Then in metaphase the mitotic spindles form and attach to cisterchromatics which align in the center. In anaphase the cisterchromatic separate and move to opposite sides and finally in telophase the cytoplasm division occurs and nuclear envelope forms. The checkpoints of mitosis phase occur between metaphase and naphase and ensures that the mitotic spindle has properly formed and cisterchromatics have properly aligned in the center. So the drugs which act in this phase are of two types. One mitotic spindle destabilizes. Example are vincristine and vinclastin. These will prevent the formation of the mitotic spindle. So as you know that formation of mitotic spindle is important for alignment of the cisterchromatics in the center. So obviously the cell will not proceed to the next phase. And second one are mitotic spindle stabilizers. That means they will not allow it to separate. So these are the vaccines. They prevent the disassembly of the microtubules. Well that's the physiological basis of action of antineuplastic drugs. If you like the video do share the video like it and subscribe to my channel Physiology Open. Thank you.