High-dose methotrexate with leucovorin rescue is a component of osteosarcoma chemotherapy. The rescue dose of leucovorin is started because methotrexate kills cells by:

• A Cross-linking DNA through alkylation of guanine residues
• B Inhibiting dihydrofolate reductase and blocking thymidylate synthesis ✓
• C Stabilising the topoisomerase II DNA cleavage complex
• D Generating interstrand cross-links after hepatic activation to phosphoramide mustard

Explanation

Methotrexate competitively inhibits dihydrofolate reductase, depleting reduced folates needed for thymidylate and purine synthesis. Leucovorin supplies reduced folate to normal tissues, rescuing them while permitting high-dose antitumour exposure. Alkylation describes cyclophosphamide and ifosfamide, topoisomerase II poisoning describes etoposide, and phosphoramide mustard is the activated alkylating species of cyclophosphamide, not related to methotrexate.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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