Drug Table - Antimetabolites Flashcards
Antimetabolites in general
Structural analogs of folic acid or of the
purine/pyramidine bases found in DNA; act
in S-phase (cell cycle specific)
Antimetabolites list
Methotrexate (Trexall) Pemetrexed (Alimta) 5-Fluorouracil (5-FU, Carac) Cytarabine (AraC, Depocyt) Gemcitabine (dFdC, Gemzar) 6-Mercaptopurine (Purinethol)
Methotrexate (Trexall) class
Folate analogs
Methotrexate (Trexall) mech
Inhibits dihydrofolate reductase (DHFR), which converts dietary folate to tetrahydrofolate (THF) needed for thymidine and purine synthesis; given orally or intrathecally
Methotrexate (Trexall) Therapeutics
Childhood ALL and choriocarcinoma; combination therapy for Burkitt's lymphoma and carcinomas of breast, ovary, head and neck, and bladder; administered intrathecally for meningeal leukemia and meningeal metastases of tumors (can't cross BBB); high-dose for osteosarcoma
Methotrexate (Trexall) Imp Side effects
Renal toxicity (crystallization in urine at high doses), hepatotoxicity (long-term, fibrosis/cirrhosis), reproductive (defective oogenesis or spermatogenesis, abortion)
Methotrexate (Trexall) Other side effects
Bone marrow (myelosuppression, spontaneous hemorrhage); GI toxicity (oral ulceration, stomatitis)
Methotrexate (Trexall) Misc
Can use leucovorin to prevent toxic
effects of MTX, as healthy cells can
take it up a lot better than tumor cells
Pemetrexed (Alimta) class
Folate analogs
Pemetrexed (Alimta) Mech
Polyglutamate forms that inhibit THFdependent enzymes (e.g., DHFR, TS); metabolized to polyglutamate forms that inhibit THF-dependent enzymes (e.g., DHFR, thymidylate synthase (TS))
Pemetrexed (Alimta) Therapeutics
Colon cancer, mesothelioma, non-small
cell lung cancer, pancreatic cancer
5-Fluorouracil (5-FU, Carac) class
Pyramidine analogs
5-Fluorouracil (5-FU, Carac) Mech
5-FU is converted to active metabolites: 5-
FdUMP inhibits TS; 5-FdUTP incorporates
into RNA & interferes with RNA function;
prodrug [capesitabine] ribosylated and phophosrylated into
5-FdUMP
5-Fluorouracil (5-FU, Carac) Therapeutics
Combination therapy for breast,
colorectal, gastric, head and neck,
cervical and pancreatic cancer;
topically for basal cell carcinoma
5-Fluorouracil (5-FU, Carac) Imp Side Effects
Hand-foot syndrome (erythema,
sensitivity of palms and soles),
cardiac toxicity (acute chest pains)
5-Fluorouracil (5-FU, Carac) Other side effects
Anorexia and nausea; mucosal
ulcerations, stomatitis, diarrhea;
thrombocytopenia and anemia
5-Fluorouracil (5-FU, Carac) Misc
Leucovorin can potentiate effects of
5-FU; must be given IV (GI toxicity
and rapid degradation + metabolism
in gut and liver)
Cytarabine (AraC, Depocyt) Class
Pyramidine
analogs
Cytarabine (AraC, Depocyt) Mech
Ara-C converted by deoxycytidine kinase to
Ara-CMP –> Ara-CTP; terminates DNA
synthesis as Ara-CTP
Cytarabine (AraC, Depocyt) Therapeutics
AML (most effective treatment), ALL
and blast phase CML
Cytarabine (AraC, Depocyt) Other side effects
Severe myelosuppression
(leucopenia, thrombocytopenia,
anemia), GI tract toxicity
(ulceration, stomatitis, diarrhea)
Gemcitabine (dFdC, Gemzar) class
Pyramidine
analogs
Gemcitabine (dFdC, Gemzar) Mech
Converted to active metabolites: dFdCDP
inhibits ribonucleotide reductase (lowers
deoxyribonucleotide); dFdCTP incorporates
into DNA, terminating DNA synthesis
Gemcitabine (dFdC, Gemzar) Therapeutics
Pancreatic cancer; effective against
non-small cell lung cancer, ovarian,
bladder, esophageal, and head and
neck cancer
Gemcitabine (dFdC, Gemzar) Other side effects
Myelosuppression (leucopenia,
thrombocytopenia, anemia), flulike
Gemcitabine (dFdC, Gemzar) Misc
More effective against solid tumors
than cytarabine
6-Mercaptopurine (Purinethol) Class
Purine analogs
antimetabolites
6-Mercaptopurine (Purinethol) Mech
Prodrug metabolized by hypoxanthineguanine
phosphoribosyl transferase
(HGPRT) to 6-thioinosinic acid (TIMP);
TIMP inhibits first step of de novo purine
base synthesis and the formation of AMP
and xanthinylic acid from inosinic acid,
reducing purine levels. As well, TIMP is
converted to thio-guanine ribonucleotides,
inhibiting DNA and RNA synthesis
6-Mercaptopurine (Purinethol) Therapeutics
Maintain remission in acute ALL
6-Mercaptopurine (Purinethol) Imp side effects
Hepatotoxicity in prolonged use
6-Mercaptopurine (Purinethol) Other side effects
Bone marrow suppression
6-Mercaptopurine (Purinethol) Misc
Drug interaction with allopurinol (for gout), which inhibits xanthine oxidase; decrease 6-MP dose to avoid drug accumulation and toxicities
