Antimetabolites Flashcards
What are antimetabolites?
Chemicals that inhibit action of metabolites therefore, INTERFERE WITH NORMAL METABOLISM
What phase of the cell cycle do antimetabolites act in
S phase: synthesis and replication of DNA
What is the two major mechanisms of antimetabolits
INHIBIT PRODUCTION of dexoyribonucleoside triphosphates (inhibits the replication of the DNA), INCORPORATE INTO THE DNA (cytotoxic effect on the cell)
What are the three different types of antimetabolites
Anti-purines, anti-folates, and anti-pyrimidines
What pathway for synthesizing DNA/RNA does tumors rely on
De novo pathway
What are the purines, pyrimidines
Adenine and guanine/ cytosine, uracil, and thymine
What are the two major anti-purines and what do they substitute for
6-mercatopurine (6-MP) –> Adenosine
6-thioguanine (6-TG) –> Guanine
What is the breaking point in the De novo purine nucleotide biosythensis
Inosine monophosphate
What are the two MOAs of anti-purines
Inhibit nucleotide synthesis at several step of de novo biosynthesis, incorporation into nucleic acids
Which antipurine blocks IMP from being converted to AMP
6-MP
T/F: When anti-purines are incorportated into DNA the repair pathways have trouble distinguishing them from regular purines but DNA/RNA polymerase never replicate them
True
What are the side effects of 6-MP
fatigue, diarrhea, nausea, skin rash, alopecia
What are the side effects of 6-TG
leukopenia, neutropenia, thrombocytopenia, anemia, anorexia
What are the two groups for anti-pyrimidines
Cytdine analogs and fluropyrimidine analogs
What are the cytdine analogs, fluropyrimindine analogs
Cytarabine and gemcitabine/ 5-flurouracil and capecitabine
What are the two MOA of 5-flurouracil
Inhibits synthesis of thymidine nucleotide (major), incorporates into RNA and DNA
What is the enzyme that interactes with 5-flurouracil not allowing for thymidine synthesis
Thymidylate synthase
What is a difference between 5-flurouracil and capectiabine that also connects the two
Capecitabine is a prodrug that to 5-FU by the liver
What tumors are most sensitive capecitabine and what cancers are usually treated by capecitabine
Tumors that overexpress thymidine phosphorylase, breast and colon cancers
Since 5-FU and capecitabine can be fatal what drugs can be given to reverse action
Uridine triacetate
Which drug contains a combination of fluropyrimidine analogs
Trifluridine/Tipiracil (TFT/TPI)
What is the MOA of TFT
The triphosphate form of TFT/TPI can be incorporated into DNA inducing DNA fragmentation, inhibits thmidylate synthase reducting the nucleotide pool levels required for DNA replication
What is the TPI MOA
Inhibits thymidine phosphorylase, increase bioavailabitly of TFT
What is the MOA of cytarabine, what type of cancer does it treat, toxicities
Incorporates into DNA and prevents DNA elongation/ leukemias/ myelosuppression, mucositis, fever, pains
What is the Dual MOA of gemcitabine, biggest setback
Inhibition of ribonuclotise reductase (ribonucleotides cannot convert to deoxy-ribonucleotides), Triphosphate form incoporates into DNA/ Half-life of 8 mins
Where does folate (vitamin B9) come from
Food (leafy greens)
What is the role of folate in thymidine synthesis
Folate aids in the co-factor N5,N10-methylene THF (essential for converting dUMP into dTMP)
What is the important co-factor in purine synthesis, how is it acquired
Formyltetrahydrofoloate, folate is converted to tetrahydrofolfate by dihydrofolate reductase (DHFR)
What is the MOA of methotrexate
Competitively Inhibits DHFR due to 1000 fold higher affinity (inhibts purine and pyrimidine synthesis)
What are the side effects of methotrexate
Memory loss (neurotoxicity), heptaotoxicity, myelosuppresion, GI toxicitites
T/F: Methotrexate is NOT safe in pregnancies
True
What medication is used as a rescue from methotrexate
Leucovorin (Folinic acid)
What category of anti-metabolite is pralatrexate, why is it special, which cancers is it used against
Anti-folate, accumulates preferentially in cancer cells and has high tumor uptake, refractory peripheral T- cell lymphoma
What are the the three enzymes that pralatrexate inhibits
DHFR, Thymidylate synthase, GARFT
