Antimetabolites Flashcards
Antifolates (2)
Methotrexate
Pemetrexed
Pyrimidine antagonists (2)
Fluorouracil
Capecitabine
Purine antagonists (2)
Mercaptipurine
Thioguanine
DNA polymerase/ DNA chain elongation inhibitors (5)
Cytarabine, Gemcitabine
Fludarabine, Cladribine, Clofarabine
Miscellaneous Antimetabolites (2)
Pentostatin
Hydroxyurea
THF
Tetrahydrofolate-> regenerated from dihydrofolate + dihydrofolate reductase
Active form of folic acid
N5, N10-methylene THF
Analog of tetrahydrofolate
*Co-factor to the thymidylate synthase *enzyme: rxn converts *substrate, deoxyuridine monophosphate (dUMP) to deoxythymine monophosphate (dTMP) and dihydrofolate
Nucleotides must be in what form to be inserted into DNA?
Triphosphate
Ternary complex
Enzyme+ substrate+ Co-factor
Thymidylate synthase+ dUMP+ N5,N10 methylene THF
5-Fluorouracil
Pyrimidine antagonist
PRODRUG: 5-fluoro dUMP is active form
5-FdUMP is false substrate that covalently binds to enzyme, thymidylate synthase preventing regeneration of THF. Ternary complex is formed
Toxicity:* stomatitis, esophagitis, GI ulceration, myelosuppression, hand and foot syndrome *
Ribonucleotide reductase
Enzyme responsible for 2’ reduction to a deoxyribose sugar
*Enzyme ONLY does 2’ reduction when nucleotide is in DIphosphate form
5-FU is catabalized by…
Dihydropyrimidine Dehydrogenase (DPD) Enzyme has polymorphisms
Leucovorin + 5-FU
Increases binding of 5-FU to thymidylate synthase
Capecitabine
Pyrimidine antagonist
PRODRUG of 5-FU: 5-fluoro dUMP is active form
Activating enzyme is *thymidine phosphorylase (removes ribose after removing carbonmate) **enzyme is upregulated in cancer cells
Toxicity: *severe diarrhea *hand and foot syndrome, myelosuppression, n/v
Resistance mechanisms to pyrimidine antagonists
- Loss or decreased activity of activating enzymes
- Increased expression or mutation of thymidylate synthase
- High levels of degradation enzymes
Methotrexate
Antifolate
MOA: pseudo irreversible inhibition of DHFR directly
Indirect inhibition of thymidylate synthase bc co factor is not regenerated ultimately inhibiting formation of dTMP
Inhibition of GAR transformylase involved in purine synthesis
*Toxicity: myelosuppression, mucositis, ulcerative stomatitis *
Maintain urine pH at 6.5 to keep drug ionized for better excretion. Unionized leads to crystalluria
Leucovorin + methotrexate
Generates folate co-factors for healthy cells. Rescues normal cells
Pemetrexed
Antifolate
MOA: inhibition of DHFR, * thymidylate synthase, *GAR transformylase
Toxicity: same as MTX; myelosuppression, mucositis, ulcerative stomatitis *
Supplement w/ B12 and folic acid instead of leucovorin for cell rescue
Resistance mechanisms to antifolates
- Impaired uptake
- Enhanced efflux
- Altered DHFR
- Increased concentration to DHFR
- Decreased polyglutamation metabolite (drug will not get trapped in cell)
Mercaptopurine, Thioguanine
Purine antagonist
MOA inhibit rate limiting enzyme in purine synthesis (amidophosphoribosyl transferase)
PRODRUGS
*activating enzyme: hypoxanthine guanine phosphoribosyl transferase HGPRT
*inactivating enzyme is TPMT (polymorphisms)
*Hypoxanthine oxidase competes w/ TPMT
Drugs can cause tumor lysis syndrome and hyperuricemia
Allopurinol
Inhibits activity of xanthine oxidase and keeps purine antagonists as xanthine and hypoxanthine. Prevents conversion to uric acid
Resistance mechanisms to purine antagonists
- Deficiency in HGPRT
Resistance mechanisms to DNA polymerase/ DNA chain elongation inhibitors
- Mutations in deoxy cytosine kinase
2. Loss of functional nucleoside transporter proteins
Hydroxyurea
Miscellaneous Antimetabolite
*MOA: inhibition of ribonucleotide reductase (enzyme converts ribose into deoxyribose when nucleotide is in Diphosphate form *
Broad anti tumor activity bc ALL nucleotides must be converted to deoxy form
