Antimetabolites
Antimetabolites are structural analogs of folate, purine, or pyrimidine substrates that block DNA and RNA synthesis in dividing cells. The class includes methotrexate, the fluoropyrimidines, cytidine and purine analogs, and hydroxyurea, and underpins first-line therapy for leukemias, lymphomas, and solid tumors, dosed with leucovorin rescue, folic acid, or pharmacogenomic testing to limit myelosuppression.
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What this article covers
- Overview
Antimetabolites structurally mimic folate, purine, or pyrimidine substrates, then either block a synthetic enzyme or are incorporated into DNA or RNA in place of the true nucleotide, halting nucleic acid synthesis.
- Epidemiology
Methotrexate anchors first-line therapy for rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis, and glucocorticoid-sparing giant cell arteritis.
- Risk factors
Renal impairment: delays clearance of high-dose methotrexate and fluorouracil metabolites.
- Pathophysiology
Methotrexate competitively inhibits dihydrofolate reductase, blocking regeneration of tetrahydrofolate, the one-carbon donor for thymidylate and purine synthesis; pemetrexed also inhibits thymidylate synthase.
- Clinical features
Class-wide myelosuppression: neutrophil and platelet nadir 7 to 14 days after dosing, recovering by day 21 to 28.
- Differential diagnosis
Alkylating agent (cyclophosphamide, cisplatin): cross-links DNA regardless of cell cycle phase, but brings hemorrhagic cystitis and gonadal toxicity antimetabolites largely lack.
- Diagnosis
There is no diagnostic test for needing an antimetabolite; the disease indication plus a pretreatment workup establish whether it is safe to start.
- Management
First, confirm eligibility: renal and hepatic function, TPMT/NUDT15 genotype before a thiopurine, and, before a teratogenic agent, a negative pregnancy test.
- Complications
Myelosuppression progressing to neutropenic fever: nadir at 7 to 14 days, treated empirically if fever develops with an absolute neutrophil count below 500/microL.
- Prognosis
High-dose methotrexate with leucovorin rescue, cytarabine-anthracycline induction, and thiopurine-methotrexate maintenance anchor curative-intent regimens for ALL, AML, osteosarcoma, and CNS…
- Prevention
Give folic acid with every methotrexate regimen: 1 mg PO once daily, or 5 to 10 mg once weekly on a nondosing day.
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