Methotrexate causes mucositis and bone marrow suppression as dose-limiting toxicities. 'Leucovorin rescue' given after high-dose MTX administration works by:
- A Providing 5-formyl THF (folinic acid) that bypasses DHFR inhibition and replenishes the reduced folate pool in normal cells — cancer cells have impaired leucovorin uptake due to reduced folate carrier downregulation ✓
- B Directly inhibiting the enzyme thymidylate synthase to prevent further MTX-induced DNA damage
- C Activating DHFR by allosteric mechanisms, restoring folate metabolism despite MTX binding
- D Increasing renal tubular secretion of MTX to rapidly clear the drug
Correct answer: A. Providing 5-formyl THF (folinic acid) that bypasses DHFR inhibition and replenishes the reduced folate pool in normal cells — cancer cells have impaired leucovorin uptake due to reduced folate carrier downregulation
Explanation
Methotrexate inhibits dihydrofolate reductase (DHFR), preventing conversion of DHF to THF and depleting reduced folates needed for purine and thymidylate synthesis. Leucovorin (5-formylTHF, folinic acid) is a pre-reduced folate that enters the folate metabolic pool without requiring DHFR activity, rescuing normal rapidly dividing cells. Tumour cells are thought to have impaired leucovorin uptake in some protocols (folate carrier downregulation) and higher intracellular MTX polyglutamate retention, allowing selective antitumour effect to persist.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.