Which rescue therapy is indicated for methotrexate toxicity?

• A. Leucovorin
• B. Penicillamine
• C. Methotrexate
• D. Deferoxamine

Answer: (A)

Leucovorin rescue is used to counteract methotrexate toxicity by providing a form of folate that bypasses the inhibited dihydrofolate reductase step. Methotrexate blocks DHFR, reducing tetrahydrofolate and halting thymidylate and purine synthesis, which damages rapidly dividing normal tissues. Leucovorin (folinic acid) is a reduced folate that can be converted directly into active folate cofactors downstream of DHFR, restoring DNA synthesis in healthy cells and thereby reducing cytotoxicity. This rescue is timed after methotrexate administration and guided by MTX plasma levels and renal function. In severe cases or delayed clearance, additional options like glucarpidase may be used to rapidly inactivate methotrexate, but leucovorin remains the standard rescue therapy. The other agents listed do not provide this protective folate rescue.