- 7/31/2024
Anti-metabolites are the important class of anti-neoplastic drugs like azithioprine, methotrexate
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00:00Antimetabolites are a diverse group of medications that are used for the treatment of various
00:06conditions, including cancer, infections, and autoimmune disorders.
00:11In this video, we are focusing on the antimetabolites used in cancer treatment.
00:16Alright, during the S phase of the cell cycle, the cell performs DNA replication.
00:24DNA is composed of a sequence of deoxyribonucleotides, and each deoxyribonucleotide is made of a
00:30phosphate group, a 5-carbon sugar like deoxyribose, and a nucleobase, which can be either a pyrimidine
00:38like cytosine or thymine, or a purine like adenine or guanine.
00:43Now, nucleotide synthesis starts with ribose 5-phosphate, which is specific for RNA, and
00:49an enzyme called ribose phosphate pyrophosphokinase uses an ATP to remove two phosphate groups
00:56from it, attaching them to ribose 5-phosphate, creating a phosphoribosyl pyrophosphate, or
01:01PRPP.
01:03Because it catalyzes the synthesis of PRPP, the enzyme ribose phosphate pyrophosphokinase
01:09is also known as PRPP synthetase.
01:14The next step is to make pyrimidines.
01:17The amino acid glutamine, bicarbonate, and water are used to form a molecule called carbamoyl
01:22phosphate which is then joined to aspartate, and together they form a ringed molecule called
01:27carbamoyl aspartic acid, which gets dehydrated to create a molecule called orotate.
01:33Next, an enzyme moves the phosphoribose unit from PRPP to orotate, and that forms erotidine
01:39monophosphate, or OMP.
01:41Next, the enzyme UMP synthase converts erotidine monophosphate into uridine monophosphate,
01:47or UMP.
01:49That UMP gets phosphorylated twice by nucleoside diphosphate kinase to become uridine triphosphate,
01:55or UTP.
01:56Finally, the enzyme CTP synthase converts uridine triphosphate into cytidine triphosphate,
02:03or CTP.
02:06Now, purine synthesis starts with the amino acids glutamine, aspartate, and glycine, together
02:11with bicarbonate and formate, which is the anion derived from formic acid.
02:17These undergo a 10-step pathway and the result is inosine monophosphate, or IMP, which is
02:22sort of a generic purine.
02:24IMP can be converted to AMP and GMP.
02:29Okay, RNA nucleotides are usually in the monophosphate form, but to get to DNA nucleotides, we need
02:36them in the diphosphate form, so CDP, UDP, ADP, and GDP.
02:42Next, an enzyme called ribonucleotide diphosphate reductase will reduce the ribose within them
02:48into deoxyribose, creating d-CDP, d-UDP, d-ADP, and d-GDP.
02:54After this, they just need to lose a phosphate group and we'll have d-CMP, d-UMP, d-AMP,
03:00and d-GMP, but something is missing, d-TMP.
03:04And here comes the folic acid, or vitamin B9, which is converted to tetrahydrofolic
03:09acid, or THF.
03:11THF acts as a mediator and accepts a methylene group from the amino acid serine and transfers
03:17it to d-UMP, or deoxyuridine monophosphate.
03:21Then, an enzyme called thymidylate synthetase can convert d-UMP to d-TMP, or deoxythymidine
03:27monophosphate, and at that point we're all set to make DNA.
03:32Now, pyrimidine rings can be degraded completely back down to carbon dioxide and ammonia, which
03:38can then be excreted from the lungs and into urine.
03:41In contrast, purine rings, or GNA, are degraded down to the metabolically inert uric acid,
03:47which is then excreted into urine.
03:52For GMP to become uric acid, the enzyme purine nucleoside phosphorylase first removes the
03:57ribose and the phosphate from it, turning it into guanine.
04:00Next, another enzyme, called guanase, removes an amino acid group, turning guanine into
04:05xanthine.
04:06Finally, xanthine is oxidized into uric acid by the enzyme xanthine oxidase.
04:14On the other hand, for AMP to become uric acid, first, the enzyme AMP deaminase removes
04:20an amine group from it, turning it into IMP.
04:23Then, purine nucleoside phosphorylase comes in and removes the phosphate and the ribose
04:28from IMP, making hypoxanthine.
04:32Hypoxanthine is then oxidized twice by xanthine oxidase, first to become xanthine, and then
04:36finally to uric acid.
04:39Now it turns out that those intermediate molecules in purine degradation, guanine and hypoxanthine,
04:45can be restored into fresh new nucleic acids through what is known as a salvage pathway.
04:51The enzyme hypoxanthine-guanine phosphoribosyltransferase, or HGPRT for short, returns ribose and phosphate
04:58back to guanine to form GMP, and to hypoxanthine to form IMP.
05:05Alright, now the cancer cells pretty much do nothing but divide all day long, and so
05:10they're very sensitive to cytotoxic medications that block DNA synthesis.
05:15The bad news is that plenty of normal cells in our body, like the cells lining the GI
05:19tract and the precursors to blood cells and platelets, are also actively dividing, and
05:23this explains why anti-cancer medications are toxic to these tissues.
05:31So the anti-metabolites usually disrupt the pathway responsible for DNA synthesis by mimicking
05:36nucleobases or folic acid and causing DNA replication and cell proliferation to come
05:41to a halt.
05:43Medications that mimic purines include azathioprine and cladribine, while medications that mimic
05:48pyrimidines include cytoterabine and 5-fluorouracil.
05:53Finally there's folic acid analogs like methotrexate.
05:58Alright, let's start with azathioprine which is the prodrug of 6-mercaptopurine or 6-MP.
06:05Azathioprine is converted to 6-MP by the enzyme thiopurine S-methyltransferase, and some 6-MP
06:11is converted to 6-thioguanine or 6-TG.
06:15Both 6-MP and 6-TG act as purine analogs and can conjugate with ribose and then get phosphorylated
06:21to form nucleotides.
06:24These nucleotides can mimic normal nucleotides and incorporate to DNA, halting DNA replication.
06:31Also, active metabolites of 6-MP inhibit two important enzymes in the purine synthesis
06:38ā PRPP synthetase and AMP deaminase.
06:42PRPP synthetase converts PRPP to IMP and AMP deaminase converts AMP to IMP, and so the end
06:50result is the decreased production of IMP which, remember, is the generic purine and
06:55thus nucleotide synthesis comes to a halt.
06:58Notice also that allopurinol, which is an anti-gout medication, inhibits xanthine oxidase
07:03which is the enzyme that metabolizes 6-MP, and when azathioprine and allopurinol are
07:08used together, 6-MP increases to toxic levels.
07:16Moving on to indications, azathioprine is used for the treatment of leukemias such as
07:21acute lymphoblastic leukemia, or ALL, and chronic myelogenous leukemia, or CML.
07:27Now, an important side effect of azathioprine is bone marrow suppression which leads to
07:31pancytopenia.
07:33When DNA synthesis is inhibited, megaloblastic anemia occurs.
07:38This and bone marrow suppression are common to all the antimetabolites used for cancer
07:42treatment.
07:43The decrease in white blood cells leads to immunosuppression, increased risk for infections,
07:48and exacerbation of chronic infections such as hepatitis B infection and herpes zoster
07:53virus infection.
07:54Other serious adverse effects include liver toxicity which manifests as cholestasis or
07:59decreased bile flow, and acute pancreatitis.
08:02Also, azathioprine is contraindicated during pregnancy due to its teratogenic effects.
08:09Acute toxic effects of azathioprine include gastrointestinal disturbances like nausea
08:13and vomiting.
08:16Now, cladribine is another purine analog which can inhibit DNA proliferation through various
08:22mechanisms.
08:24Cladribine gets phosphorylated to a triphosphate form which can be incorporated into newly
08:28synthesized DNA strands.
08:31Cladribine can also inhibit DNA polymerase, the key enzyme of DNA replication.
08:36Either way, DNA synthesis comes to a halt.
08:39Cladribine is also resistant to adenosine deaminase which is the enzyme that normally
08:43degrades purines, so it can reach very high levels inside the cells, decreasing the de
08:48novo purine synthesis.
08:50Moving on to indications, cladribine is the drug of choice for hairy cell leukemia and
08:54it can also be used for other types of leukemias.
08:58Side effects include bone marrow suppression and megaloblastic anemia.
09:03Alright, now let's move on to pyrimidine analogs.
09:07Cytarabine gets phosphorylated to RSCTP, a triphosphate metabolite that binds and competitively
09:12inhibits DNA polymerase and thus, DNA synthesis.
09:17Cytarabine is indicated for hematologic malignancies like leukemias and lymphomas.
09:22The main side effect of cytarabine is bone marrow suppression with megaloblastic anemia
09:26like the purine analogs.
09:31Now 5-fluorouracil or 5-FU is a pyrimidine analog that interferes with the folic acid
09:37cycle.
09:385-fluorouracil gets metabolized to its active form which is 5-FDUMP and forms a complex
09:44with THF.
09:46This complex can inhibit thymidylate synthase which normally binds to DUMP and converts
09:51it to DTMP.
09:53Inhibition of thymidylate synthase results in decreased synthesis of thymidine which
09:57is a DNA component.
09:59Other active metabolites of 5-fluorouracil can also be incorporated into DNA and RNA
10:05resulting in inhibition of DNA and RNA synthesis.
10:11Now unlike the other antimetabolites, 5-fluorouracil is indicated for solid tumors rather than
10:17hematologic malignancies.
10:19Common indications include colorectal cancer and pancreatic cancer, but it's also indicated
10:24for head and neck cancer, breast cancer, ovarian cancer, bladder cancer, and hepatocellular
10:30cancer.
10:31What's more, 5-fluorouracil can also be applied topically for the treatment of basal
10:35cell carcinoma.
10:37Now keep in mind that the effects of this medication can be enhanced with the addition
10:41of leucovorin which is also called folinic acid and it's a reduced form of folic acid.
10:47Moving on to the adverse effects.
10:49Like the rest of the antimetabolites, 5-fluorouracil can cause bone marrow suppression and mega
10:54globlastic anemia.
10:56Other side effects include gastrointestinal disturbances like severe diarrhea, mucositis,
11:01alopecia, CNS toxicity, cutaneous reactions such as photosensitivity, and palmar-planter
11:08erythrodysesthesia or hand-foot syndrome.
11:11Now in the case of an overdose, uridine can be an effective antidote.
11:16Finally, an important antimetabolite is methotrexate which is a folic acid analog.
11:22DHFR normally converts DHF to THF which provides methyl groups necessary for the synthesis
11:28of dTMP from dUMP and for purine synthesis.
11:32Now, methotrexate has a higher affinity than DHF for DHFR and so it binds and irreversibly
11:39inhibits this enzyme, resulting in decreased levels of THF.
11:43THF is also involved in the synthesis of purines and amino acids as well.
11:48The result is a decrease in the synthesis of DNA, RNA, and proteins and thus inhibition
11:53of cell division.
11:56Alright, methotrexate can be used for the treatment of leukemias, especially acute lymphoblastic
12:04leukemia or ALL, lymphomas such as primary CNS lymphoma and non-Hodgkin's lymphoma,
12:10as well as solid tumors like breast cancer, head and neck cancer, and bladder cancer.
12:15Also, methotrexate can be used for conditions where there is abnormal proliferation of trophoblastic
12:21tissue.
12:22It's the drug of choice for early unruptured ectopic pregnancy and choriocarcinoma which
12:27is a germ cell tumor.
12:29Apart from its use as an anti-cancer agent, methotrexate is also used for inflammatory
12:34conditions like rheumatoid arthritis, psoriasis, inflammatory bowel disease, systemic lupus
12:40erythematosus, and dermatomyositis.
12:46Now, let's move on to side effects.
12:49Like all the antimetabolites, the major side effect of methotrexate is bone marrow suppression
12:53and megaloblastic anemia.
12:55The good news is that myelosuppression can be reversed with folinic acid or leucovorin
13:00and this strategy is called leucovorin rescue.
13:04Leucovorin is already a reduced form of folic acid and thus it doesn't require dihydrofolate
13:09reductase to get activated.
13:11Also, leucovorin reverses the action of methotrexate by displacing it from its binding sites.
13:17Another important side effect of methotrexate is liver toxicity which manifests as macrovesicular
13:22fatty change, a severe form of hepatic steatosis where fat vesicles displace the nucleus to
13:28the periphery of the hepatocyte, and pulmonary toxicity which manifests as pulmonary fibrosis.
13:35Also, use of methotrexate in pregnancy can lead to neural tube defects and congenital
13:40heart defects.
13:41So, methotrexate is contraindicated in pregnancy and characterized as category X.
13:47Other side effects include alopecia and mucositis.
13:52Now let's make a simple and fun mnemonic that'll help you efficiently memorize these
13:56pharmacology facts.
13:58We can set the scene in a port city.
14:01The stormy ocean with its pouring rain is where we'll put the purine analogs, the city
14:05with its large pyramid will contain the pyrimidine analogs, and behind the city there's a nice
14:10field for frolicking for the folic acid analogs.
14:16Now in the stormy sea, we have a 19th century iron-clad battleship for cladrobine.
14:22On top of the ship, there's a majestic zebra prince for azathioprine.
14:28Since both are used to treat leukemia, a cancer of the blood and bone marrow, let's paint
14:32a bone with a crab eating the marrow on the side of a ship.
14:36Azathioprine is the drug of choice for hairy cell leukemia, so we can also have some hair
14:40growing out of the gun turrets of the ironclad.
14:43For side effects, we can put some broken bones floating in the ocean for bone marrow suppression,
14:48and there's a bomb with a red blood cell drawn on it for megaloblastic anemia.
14:53Azathioprine causes liver damage and pancreatitis, so we'll have the zebra prince toss a damaged
14:58liver inside a flaming frying pan into the sea.
15:02This drug is also teratogenic, so let's have the zebra's pregnant wife scold him
15:06for polluting.
15:08Okay, let's head to the city for the pyrimidine analogs.
15:13First, notice that the largest building in the city is arabic-styled for cytarabine.
15:19Five flower girls are coming out of his building to welcome the return of the prince, and they
15:23represent 5-fluorouracil.
15:26Cytarabine is used to treat leukemia, so let's put a big flag on the building with the same
15:30crab-eating bone marrow design as seen on the ironclad.
15:34On the flagpole, there's a little bump that looks like a lymph node.
15:38There's a little crab hanging off of it since this drug can also treat lymphomas.
15:425-fluorouracil is only used to treat solid tumors, so the five flower girls are dragging
15:47a large solid stone crab statue.
15:50The crab is wearing sunglasses and holding a bottle of suntan lotion to help you remember
15:54basal cell carcinoma.
15:57Since the side effects of both drugs include bone marrow suppression and megaloblastic
16:01anemia, let's put the bomb and the broken bones between the girls and the building.
16:06For the drug-specific side effects for 5-fluorouracil, let's have one of the girls wearing sunglasses
16:11for photosensitivity.
16:13The girl next to her is holding a toilet for severe diarrhea.
16:16The next girl is holding a brain in a jar for neurotoxicity, and the fourth girl has
16:21large swollen hands and feet for hand-foot syndrome.
16:24The last girl's got a big smile on her face since she has the antidote uridine.
16:29So she's carrying a urinal with dinner plates in it.
16:32Finally, let's head to the fields of frolicking for our folic acid analogs.
16:40Under a tree, there's a T. rex teaching math for methotrexate.
16:45It's standing on a stone crab statue since it's effective against solid tumors, and
16:49it's holding a bone with a crab eating the marrow for leukemias.
16:53A crab is pinching a lymph node on its neck for lymphomas.
16:56On the tree, there's a fruit that looks kind of like a fetus to help you remember
17:00it's used for ectopic pregnancies.
17:03On the same branch, there's a bunch of little crabs singing in a choir for choriocarcinoma.
17:08The dinosaur's little claws are on fire to help you remember it's also used to treat
17:12inflammatory conditions like rheumatoid arthritis.
17:15For side effects, let's look at the students sitting around the tree.
17:19One's holding a broken bone, and the bomb with a red blood cell, just like the ones
17:23we saw in the other areas.
17:25The kid next to him also has a broken bone, but luckily he's got a warranty, so he's
17:29smiling.
17:30This is a reminder that leukovarin, or lucky warranty, can reverse the bone marrow suppression
17:35caused by methotrexate.
17:37The kid next to him is holding a damaged liver, with a strip of bacon on top for hepatic steatosis,
17:42and the last kid dozed off, so a spider is building a web on his chest for pulmonary
17:46fibrosis.
17:48His pregnant mother is yelling at him to wake up, and also to help you remember that
17:52this drug is teratogenic.
17:54Alright, as a quick recap, the antimetabolites used for cancer treatment include azathioprine
18:03and cladribine which are purine analogs, cytarabine and 5-fluorouracil which are pyrimidine analogs,
18:09and methotrexate which is a folic acid analog.
18:12They all inhibit DNA synthesis and so they act in the S phase and are cell cycle specific.
18:19Azathioprine is used for the treatment of leukemias.
18:22Cladribine is the drug of choice for hairy cell leukemia.
18:26Cytarabine is indicated for hematologic malignancies like leukemias and lymphomas.
18:305-FU is indicated for solid tumors like colorectal cancer and pancreatic cancer, but it's also
18:36indicated for head and neck cancer, breast cancer, ovarian cancer, bladder cancer, and
18:41hepatocellular cancer.
18:435-FU can also be applied topically for the treatment of basal cell carcinoma.
18:49Methotrexate can be used for leukemias, lymphomas, as well as solid tumors.
18:52Also, it's the drug of choice for early, unruptured ectopic pregnancy and for choriocarcinomas.
18:59The major side effect of all the antimetabolites used for cancer treatment is bone marrow suppression,
19:04but in the case of methotrexate, it can be reversed with leucovorin.
19:13But wait!
19:14There's more!
19:15Here's a mind map with all of the mnemonics.
19:18Go ahead and pause the video so you can test yourself to see what you remember.
19:22Stay tuned for the answers after the credits.
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