Question
Methotrexate
Answer
Methotrexate is a folate-antagonist antimetabolite, cell-cycle-specific (S-phase).
MOA: methotrexate → competitively inhibits dihydrofolate reductase (with very high affinity) → blocks tetrahydrofolate regeneration → halts purine and thymidine synthesis → arrests DNA replication. Leucovorin (folinic acid) rescue — administering already-reduced folate that bypasses the blocked reductase step — allows higher, more effective doses while rescuing normal host cells from lethal antifolate toxicity.
Uses: acute lymphoblastic leukemia, lymphomas, choriocarcinoma (single-agent curative), osteosarcoma; at much lower, non-oncologic doses — rheumatoid arthritis and psoriasis (immunomodulatory rather than cytotoxic use).
Adverse effects: bone marrow suppression, mucositis, hepatotoxicity, nephrotoxicity (crystallizes in renal tubules at high doses), teratogenicity, pulmonary fibrosis with chronic low-dose use.