High-dose methotrexate with folinic acid (leucovorin) rescue is part of osteosarcoma chemotherapy. Leucovorin rescue spares normal tissues because:
- A It supplies reduced folate that bypasses the dihydrofolate reductase blocked by methotrexate ✓
- B It accelerates renal clearance of methotrexate by competing for tubular secretion
- C It irreversibly binds methotrexate in the plasma
- D It upregulates thymidylate synthase in tumour cells only
Correct answer: A. It supplies reduced folate that bypasses the dihydrofolate reductase blocked by methotrexate
Explanation
Methotrexate kills cells by inhibiting dihydrofolate reductase, depleting reduced folates needed for thymidylate and purine synthesis. Leucovorin is 5-formyl tetrahydrofolate, a fully reduced folate that enters normal cells through the reduced folate carrier and restores DNA synthesis without needing dihydrofolate reductase. Rescue is timed after methotrexate dosing and guided by serum methotrexate levels, continuing until levels fall below about 0.1 micromol/L.
Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.
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