A 58-year-old woman receiving irinotecan for metastatic colorectal cancer develops profuse watery diarrhoea beginning more than 24 hours after her infusion, along with neutropenia. The cytotoxic action of irinotecan responsible for these effects is:

• A Formation of a ternary complex with dihydrofolate reductase
• B Inhibition of topoisomerase II, causing double-strand DNA breaks
• C Inhibition of thymidylate synthase, blocking dTMP synthesis
• D Inhibition of topoisomerase I, causing single-strand DNA breaks ✓

Explanation

Irinotecan is a prodrug converted to SN-38, a potent inhibitor of topoisomerase I. Failure to religate cleaved single DNA strands leads to replication-dependent double-strand breaks and cell death. Topoisomerase II inhibitors are the epipodophyllotoxin etoposide and anthracyclines. Thymidylate synthase inhibition defines fluoropyrimidines such as 5-FU, and dihydrofolate reductase inhibition defines methotrexate, neither of which applies here.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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