A 28-year-old woman with newly diagnosed acute lymphoblastic leukaemia (ALL) is started on high-dose methotrexate (MTX) chemotherapy. The structure marked **A** in the diagram is the primary target of methotrexate. Which of the following best explains the mechanism by which methotrexate toxicity is managed in this patient, and why folinic acid (leucovorin) is administered as rescue therapy?

Explanation

## Why folinic acid (leucovorin) is the correct rescue agent Methotrexate irreversibly inhibits dihydrofolate reductase (DHFR), blocking the regeneration of tetrahydrofolate (THF) from dihydrofolate. This impairs both purine and thymidylate synthesis, causing S-phase cell cycle arrest in rapidly dividing cells (cancer cells and normal bone marrow, GI mucosa). Folinic acid (citrovorum factor) is the reduced, active form of folate that **bypasses the DHFR block entirely** — it does not require DHFR-mediated conversion and directly provides the THF cofactor needed for one-carbon transfer reactions. This allows normal cells to recover while cancer cells, which have already incorporated MTX and cannot access this bypass, remain growth-arrested. This is the basis of "rescue" therapy in high-dose MTX protocols (as used in ALL, choriocarcinoma, and osteosarcoma). The timing and dose of leucovorin are critical: given 24–48 hours after MTX, it rescues normal tissue toxicity without compromising the anti-tumour effect. ## Why each distractor is wrong - **Option 0 (DHFR inhibition by folinic acid)**: Folinic acid does not inhibit DHFR; it is a substrate that bypasses the need for DHFR activity. It does not prevent MTX binding or compete with MTX at the enzyme active site. - **Option 2 (Competitive displacement)**: Folinic acid does not displace methotrexate from DHFR. MTX binding to DHFR is essentially irreversible. Leucovorin works by circumventing the block, not by removing MTX from the enzyme. - **Option 3 (Urinary alkalinization)**: While vigorous IV hydration and urinary alkalinization (using sodium bicarbonate) are essential supportive measures to prevent MTX nephrotoxicity by reducing precipitation in renal tubules, this is a separate toxicity-prevention strategy. Folinic acid's primary rescue mechanism is metabolic (THF provision), not renal clearance enhancement. **High-Yield:** Folinic acid = pre-formed THF = bypasses DHFR block; methotrexate = DHFR inhibitor = blocks THF regeneration. Leucovorin rescue works only if given after MTX has exerted its cytotoxic effect on cancer cells. [cite: KD Tripathi 9e Ch 62 (Antimetabolites); Harper 32e Ch 34 (Folate Metabolism & Antifolates)]