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20 Cards in this Set

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antimetabolites MOA?
competing with natural substrate, block biosynthesis of nuleic acid in DNA or RNA
activated to ara-CTP incorporated into DNA prevent elongation, competitive inhibitor of DNA polymerase alpha, beta and gamma affecting replication and repair, good CSF penetration
CYTARABINE or cytosine arabinoside or ara-C
RENAL elimination (decreased with NSAIDs, ASA, probenecid and penicillin), water soluble and tubular secretion enhanced by Sulfonamides and Ceftriaxone, <> t1/2 increase in patients with pleural effusion or ascites = toxic, <> can penetrate CSF at high dose
METHOTREXATE
antimetabolites with NEUROTOXICITY
METHOTREXATE
5-FU
enzyme inhibited by 5-FU and METHOTREXATE
Thymidylatre Synthase
MTX: 80% gets polyglutamated become active to inhibit both purine and pyrimidine synthesis<>reduce conversion of dUMP to dTMP indirectly through inhibition of DHRH (unlike 5-FU) leading to accumulation of dUMP that block DNA synthesis <>direct inhibition of DHFR dihydroxyfolate reductase depleting stores of tetrahydrofolate and acumulate DHF (also block TS) enter cells via folate active transporter <> single and double strand break with impaired repair
5-FU: after several conversions, 5-FU becomes 5-dUMP and in presence of reduced folate will inhibits TS thymidylate synthetase, leading to depletion in dTMP <> may also be converted to FdUMP or FUTP and incorporated into DNA or RNA
myelosuppression (increase with IV bolus), N&V, diarrhea, mucositis, alopecia, when infused: neurotoxicity [esp. women because lower expression of DPD catabolitic enzyme, but also more effective Tx] and hand&foot syndrome (palm and sole desquamation), in patients that lack the 5-FU metabolizing enzyme, it will present like an allergy
5-FU (fluorouracil), ftorafur, FUDR, UFT, Capecitabine
pancreatic cancer
GEMCITABINE
very active in pancreatic cancer (1st choice), non-small cell lung cancer, lymphoma, nasopharyngeal cancer
antimetabolites used in breast cancer
METHOTREXATE
PERMETREXED
5-FU
purine analogs
6-MP (mercaptopurine)
6-TG (thioguanine)
ANTIFOLATES
METHOTREXATE
PEMETREXED
RALTITREXED
FLUOROPYRIMIDINES
5-FU (fluorouracil), ftorafur, FUDR, UFT, Capecitabine
Adenosine deaminase inhibitor
DEOXYCOFORMYCIN
active against hairy cell leukemia
ADRs of DEOXYCOFORMYCIN
cytotoxic by accumulation of dATP, myelosuppression, nausea, rash
Immunosuppression, myelosupperssion and fever
CLADRIBINE or 2-CDA (chlorodeoxyadenosine)
LEUCOVORIN used with what drugs?
GOOD with MTX: competes with DHF for DHFR binding, so require excess free Mtx <>inhibitor of tubular secretion such as aspirin or probenecid decrease renal clearance of Mtx while sulfonamides and ceftriaxone enhance tubular secretion; <> use LEUCOVORIN rescues normal cells from toxic effects of Mtx by restoring folate stores and competing with Mtx to overcome TS inhibition

BAD WITH 5-FU: to be given before MTX (will decrease MTX activity) because if MTX given before 5-FU will increase 5-FU toxicity due to increased PRPP which enhances formation of FUTP <> pretreat with LEUCOVORIN increases 5-FU toxicity due to increase in ternary complex formation
how does resistance to METHOTREXATE come about?
resistance because of amplification of DHFR gene (most common), reduction in folate transport, decreased capacity for polyglutamate, and alteration in target enzyme DHFR
antimetabolites that cause myelosuppression
METHOTREXATE
PEMETREXED
RALTITREXED


5-FU (fluorouracil), ftorafur, FUDR, UFT, Capecitabine

CYTARABINE or cytosine arabinoside or ara-C
GEMCITABINE
azacytidine

6-MP (mercaptopurine)
6-TG (thioguanine)


ara-A
FLUDARABINE
azathioprine
CLADRIBINE or 2-CDA (chlorodeoxyadenosine)

DEOXYCOFORMYCIN
6-MP (mercaptopurine)
6-TG (thioguanine)
taken up into DNA causing single strand breaks (triphosphate form), activated into monophosphate form by HGPRT leading to inhibition of purine synthesis, cross BBB poorly
PEMETREXED 's MOA?
inhibit TS, DHFR and GARFT glycinamide ribonucleotide formyltransferase more than Mtx, all folate dependent enzymes involved in de novo biosynthesis of T and purines G+A
first choice for choriocarcinoma
METHOTREXATE