Pharmacology - Chemotherapy agents (MOA, Alkalating, antimetabolites, topoisomerase, antimitotic )

cancer treatment is divided into four main types surgical radiation therapy chemotherapy and biologic therapy now the goal of cancer treatment is to eradicate the cancer every cancer treatment has the potential to cause harm and treatment may be given that produces toxicity with really no benefit in this video we're gonna talk about chemotherapy agents and their mechanism of action chemotherapy agents have different mechanism action and target different parts of the cell cycle combinations of these chemotherapy agents are preferred because different mechanism action means that they work on different parts of the cell cycle which means that

overall less side effects in order to understand how chemotherapy drugs chemotherapy agents work we firstly have to revise the cell cycle the cell cycle has four phases the growth one phase or the g1 phase where the organelles duplicate the S phase which is where the DNA basically replication occurs the growth 2 phase is when the cell prepares itself for the M phase which is mitosis where the cell divides into two identical daughter cells then the cell cycle will repeat itself we can further explore mitosis mitosis has other phases the prophase is where the centrosome duplicates

and form these microtubules in metaphase the chromosomes the DNA really align in the middle of the cell and the microtubules that were formed from the centrosome attach to the centromeres which are the center points of the chromosomes in anaphase the chromosomes are separated and reach either end of the cell in chilla phase the cell membrane constricts ready to separate and then a new nuclear membrane is being formed the cell cycle is a continuous process and so you have checkpoints during the cell cycle to make sure that there are no abnormalities in the cell before it

progresses to each phase these checkpoints include the g1 checkpoint the g2 checkpoint and the M phase checkpoint one thing these checkpoints look at is whether there are abnormalities damage or mutations to the DNA for example DNA is a double helix structure composed of four nucleotides after the g1 phase where the organelles are duplicate comes the S phase now in the S phase DNA becomes replicated now let's revise this process during replication the DNA strand is separated by an enzyme called helicase during the unwinding of DNA tension can occur distally the tensions are these coils that

are being formed the cells have a normal biological mechanism to fix these coils and super coils that are being formed this mechanism is an enzyme called topoisomerase here topoisomerase to fixes these super coils reducing the tension in the DNA strand and we'll talk about topoisomerase later on now there are four types of nucleotides as mentioned in DNA these nucleotides can be divided into two groups pyrimidine and purine pyrimidine includes thymine and cytosine and purines include adenine and guanine so what happens is a double-stranded DNA gets unwind by helicase into two separate strips another enzyme called

DNA polymerase will create a new strand on both strips the new strand following the helicase is the leading strand the lagging strand is the Strand that is created in segments chemotherapy agents target different parts of the cell cycle as mentioned because of this they are grouped into different classes let's take a look at the different classes one at a time first let's begin with alkylating agents the oldest anti-cancer cytotoxic s-- now these agents are antiproliferative drugs they work by binding covalently via alkyl groups to DNA they then form cross links and thought to arrest the

cell cycle in the g1 or the S phase of the cell cycle now the alkylating agents actually bind to the nucleotide guanine once bound they form cross linkage of DNA strands broken or cross-linked DNA is intrinsically unable to complete normal replication or cell division so they undergo cell arrest they stop because they're in cell arrest the cell will then either be repaired so it can proceed progress through the cell cycle or this cell will undergo apoptosis basically dying examples of drugs in the class of alkylating agents include nitrogen mustards such as cyclophosphamide and there's also

cisplatin now cisplatin is an interesting drug it is one of the most active anti-cancer drugs and used on many types of cancers but also come with many toxicities it is it is actually its own class but has similar mechanism of action to alkylating agents and so it is put in this category the next class of chemotherapy agents are the anti metabolites or the antimetabolites these guys interfere with normal cell metabolism of nucleic acids so really they disrupt DNA RNA metabolism production interrupting the S phase of the cell cycle we will focus on DNA metabolism here

and the four nucleotides for DNA are thymine cytosine adenine and guanine of which thymine is strictly DNA I mean the DNA nucleotide is made after a series of reactions one important reaction is from D UMP to D TMP this reaction is carried out by an enzyme called fireman delayed synthase for D UMP to convert to dtmp requires a co-current reaction which phiman delayed synthase also carries out this is the conversion between methylene tetrahydrofolate to dihydrofolate so Thermolite synthase catalyzes methylene tetrahydrofolate and D UMP to form dihydrofolate and the TMP dihydrofolate is converted to tetrahydrofolate by

another important enzyme dihydrofolate reductase tetrahydrofolate becomes methyl tetrahydrofolate once again so this whole reaction involving these two enzymes thermo delayed synthase and dihydrofolate reductase it's important in order to make DNA by interrupting any of these two enzymes you are essentially disrupting thymine thymidine synthesis and thus DNA synthesis a few chemotherapy agents work here these include five floral uracil which inhibits the mid-late synthase and also specific time a delayed synthesis inhibitors a very common drug used in rheumatoid arthritis also is a chemotherapy drug and an ectopic pregnancy drug this drug is methotrexate and it works by

inhibiting dihydrofolate reductase other chemotherapy agents that work specifically on disrupting purine metabolism and synthesis include or CAPTA purine and theö guanine here in summary antimetabolites work by disrupting DNA RNA metabolism and production and thus it will disrupt cancer cells from progressing through the cell cycle the next class are anti-tumor antibiotics main ones include a group called anthracyclines these antibiotics have several mechanism of action but their specific mechanism action is unclear one effect is at these anti-tumor antibiotics inhibits topoisomerase to remember topoisomerase are important enzymes in maintaining the structure that topology of DNA topoisomerase to remember

relaxes super coils by breaking two DNA strands unwinding it relaxing it and then attaching it back together once it's unwound and so by inhibiting topoisomerase DNA doesn't relax and so replication becomes hard with the super coils or maybe the topoisomerase breaks the DNA strand but then can't really attach it back together either way DNA replication is inhibited and the cell doesn't progress through the cell cycle another way antibiotics work is by inhibiting helicase the enzyme which unwinds the DNA by inhibiting this enzyme you inhibit DNA replication finally antibiotics such as anthracyclines induce reactive oxygen species

formation causing destruction of the cell and triggering apoptosis examples of anthracyclines include doxorubicin and donor ribbon the next class of chemotherapy drugs are the topoisomerase inhibitors topoisomerase remember our essential enzymes in regulating the topology of DNA helix there are two types of topoisomerase there's top are summaries one and there's topoisomerase to which we have already talked about topoisomerase one cleaves only one strand of the DNA and relaxes DNA coil during replication example is here is a DNA double helix the top where somewhere is one will click one strand and then unwind it and attach it

causing one less coil topoisomerase to as mentioned cleaves two strands of the DNA helix and relaxes supercoils during DNA replication which again we've already talked about topoisomerase one inhibitors inhibit topoisomerase one and thus inhibits the relaxation of DNA and thus potentially inhibits proper DNA replication example of this chemotherapy agent is cam 2 thus in topoisomerase two inhibitors we already talked about and include etoposide you the next chemotherapy class work on the M phase of the cell cycle and are called the anti microtubule agents these guys disrupt the M phase of the cell cycle leading to

cell arrest which then will lead to apoptosis these are the taxanes and the vinca alkaloids let's just quickly recap the M phase to understand how these anti microtubule agents work the M phase consists of the prophase metaphase anaphase and telophase during early mitosis microtubules are extending from the centrosomes and attach to the centromeres of the chromosome the microtubules allow for the separation of duplicated DNA into either side of the cell before the microtubules start degrading and breaking down vinca alkaloids inhibit microtubule assembly or formation and so are known as microtubule destabilizes without no microtubules forming

this will disrupt the M phase causing cell arrest the other group of anti microtubules are the taxanes these guys bind to and stabilize the microtubules that are already formed in the M phase and so these guys are called the microtubule stabilizers they basically inhibit the breakdown of the microtubules once they are formed and so you don't complete the M phase of the cell cycle which means you get M phase arrest you get cell arrest the other important class of chemotherapy agents are the hormonal agents which are not discussed here because there are many times hopefully

a separate video will look into this thank you for watching I hope this helped thank you for watching finally it's very important to understand the side effects of chemotherapy agents I have a separate video on that which looks at the side effects the acute side effects of chemotherapy agents thank you for watching