A 50-year-old man with metastatic colorectal cancer is treated with 5-fluorouracil (5-FU). The oncologist adds leucovorin to the regimen. What is the rationale for this combination?

• A Leucovorin rescues normal cells from 5-FU toxicity
• B Leucovorin increases 5-FU absorption from the gut
• C Leucovorin stabilises the ternary complex of FdUMP with thymidylate synthase, enhancing cytotoxicity ✓
• D Leucovorin prevents 5-FU-induced cardiotoxicity

Explanation

5-FU is converted intracellularly to FdUMP, which binds thymidylate synthase (TS) and blocks dTMP synthesis, ultimately inhibiting DNA replication. Leucovorin (folinic acid) donates the folate cofactor (5,10-methylene THF) that stabilises the covalent ternary complex between FdUMP, TS, and the folate, greatly prolonging TS inhibition and enhancing cytotoxicity. High-dose leucovorin is used to rescue methotrexate toxicity in normal cells, not 5-FU. Leucovorin has no direct effect on GI absorption or cardiotoxicity of 5-FU.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.