In suspected methotrexate overdose, which rescue agent is used to counteract toxicity?

• A. Leucovorin (Folinic acid)
• B. Vitamin C
• C. Activated charcoal
• D. N-acetylcysteine

Answer: (A)

Rescue therapy with leucovorin (folinic acid) is used after methotrexate to prevent toxicity by bypassing the blocked dihydrofolate reductase enzyme. Methotrexate inhibits DHFR, which stops production of reduced folates needed for DNA synthesis in rapidly dividing cells, leading to toxic effects in bone marrow and the GI tract. Leucovorin provides a usable form of folate that does not require DHFR to become active, supplying normal cells with the folate needed for thymidylate and purine synthesis while MTX continues to exert its anti-cancer effect in malignant cells. The timing and dose of leucovorin are guided by MTX plasma levels and patient factors, with the goal of rescuing normal tissues without negating MTX’s therapeutic action.

Vitamin C has no role as a specific rescue agent for MTX toxicity. Activated charcoal is a decontamination strategy for certain ingestions but is not a rescue treatment for MTX toxicity. N-acetylcysteine is the antidote for acetaminophen overdose, not methotrexate.