Methotrexate plus 5-fluorouracil is associated with which toxicity?

• A. Neurotoxicity
• B. Myelosuppression
• C. Hepatotoxicity
• D. Ototoxicity

Answer: (B)

Combining methotrexate with 5-fluorouracil predominantly risks bone marrow suppression because both drugs disrupt DNA synthesis in rapidly dividing cells, and the bone marrow is highly sensitive to this effect. Methotrexate inhibits dihydrofolate reductase, depleting tetrahydrofolate and blocking purine and thymidylate synthesis. 5-fluorouracil inhibits thymidylate synthase, reducing dTMP and further crippling DNA replication. When used together, their cytotoxic effects on hematopoietic precursors add up, leading to myelosuppression with drops in white cells, red cells, and platelets. This is the dose-limiting and most clinically prominent toxicity for this combination, necessitating careful monitoring of blood counts and supportive care. Other toxicities like neurotoxicity, hepatotoxicity, or ototoxicity can occur with these or other regimens, but they are not the defining risk of this particular combination.