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21 Cards in this Set
- Front
- Back
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Antimetabolites target what cell cycle phase?
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S-phase specific
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Which 4 antimetabolites mainly deplete essential metabolites?
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MTX, 5FU, MP, hydroxyurea
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Which 2 antimetabolites mainly incorporate into DNA?
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araC, 6TG
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What is inosinic acid? 2) What is required for its synthesis? 3) What is orotic acid?
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precursor for purines. 2) a tetrahydrofolate coenzyme. 3) precursor for purines. Note FH4 is NOT required for this
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What does hydroxyurea inhibit? Implication (2)?
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Ribonucleotide reductase. 2) inhibits: UDP -> dUDP and CDP -> dCDP
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MTX targets what? 2) Result? 3) Why are the results self-limiting?
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1) DHFR. 2) depletes cellular pool of N5,10-methlenetetrahydrofolate required for conversion of dUMP to dTMP. 3) MTX inhibits RNA and protein synthesis, cell growth, so it all slows down
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MTX transport? 2) What keeps it from coming out?
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Actively taken up into cells by saturable transport system that also transports folate. 2) folic acid and MTX are polyglutamylated in cell -> increases their affinity for DHFR and "traps" them in cell
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MTX and osteogenic sarcoma?
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Treat with very high doses of MTX which causes cancer cells to get MTX through diffusion (they have folate transporter problems). Normal cells would die so "rescue" with low dose of leucovorin. This is converted in two steps to N5, 10-methylenetetrahydrofolate
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MTX has what main resistance mechanism? 2) Intrathecal?
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Decreased uptake. 2) MTX penetrates CSF poorly, so intrathecal allows for prophylaxis and treatment of leukemic meningitis
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MTX slow metabolism/tubular secretion has what affect with other drugs? 2) High dose regimens cause what?
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Things that reduce blood flow (NSAIDs), are nephrotoxic (cisplatin, ampho. B, gentamycin) or weak organic acids can crank the toxicity. Note other drugs can displace MTX from plasma proteins too. 2) metabolite hydroxymethotrexate adds up and can cause renal failure
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MTX indication (4 big, one catchall)
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childhood ALL, choriocarcioma, severe psoriasis, refractory rheumatoid arthritis. 2) carcinomas of breast, head, and neck
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5FU. Activation? 2) MOA? 3) Distribution
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Converted to FdUMP. 2) forms stable ternary complex with thymidylate synthetase and methylene FH4 to inhibit production of dTMP. 3) all tissues including CNS
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Interaction beween 5FU and leucovorin? 2) Why is this interesting?
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Leucovorin enhances efficacy of 5FU by promoting the formation of the ternary complex. 2) Interesting b/c Leucovorin inhibits MTX.
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5FU inactivation? 2) Use (4)
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Liver inactivation (to which some enzyme deficiency). 2) carcinomas of breast and GI tract (Colon!). Also topically for keratoses and basal cell carcinomas
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Cytosine Arabinoside (araC). 1) Analog? 2) MOA? 3) Activation? 4) Inactivation?
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1) deoxycytidine. 2) inhibits DNA synthesis by incorporating into DNA -> causes mis-stacking of bases. 3) must be activated to araCMP by deoxycytidine kinase. 4) inactivated to araU by cytidine deaminase
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araC. 1) Distribution? 2) Use?
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1) penetration of CSF after iv admin. 2) AML
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Mercaptopurine and 6-Thioguanine. 1) Analogs? 2) Activation to and by what?
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1) hypoxanthine and guanine. 2) thioIMP and thioGMP by HGPRTase
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Mercaptopurine . 1) MOA? 2) Inactivation? 3) Implication?
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1) inhibitor of the first step of purine biosynthesis. 2) inactivated in liver to 6-thiouric acid by xanthine oxidase. 3) Allopurinol would cause this drug to be more toxic!
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MP has what two major mechanisms of resistance? 2) Indication (2)
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1) Deficiency of HGPRTase -- cross resistance to 6-TG. 2) Increased alkaline phosphatase activity. 3) maintenance therapy of ALL and CML
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Thioguanine (6-TG) and DNA? 2) Interaction with allopurinol? 3) Indication?
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1) incorporates into DNA. 2) No dose reduction with allopurinol as very little is converted to 6-thiouric acid. 3) induce remission in acute granulocytic leukemia
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Hydroxyurea primary use? 2) Another use?
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1) management of myeloproliferative disorder including Chronic Granulocytic Leukemia. 2) Radiotherapy since it synchronizes cells at G1/S
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