The cytotoxic action of etoposide is best explained by which of the following mechanisms?

• A Stabilization of the topoisomerase II DNA cleavable complex leading to double-strand breaks ✓
• B Inhibition of dihydrofolate reductase with depletion of thymidylate
• C Intercalation between DNA base pairs with inhibition of topoisomerase I
• D Generation of free radicals that cause single-strand DNA breaks

Explanation

Etoposide poisons topoisomerase II by stabilizing the transient cleavable complex formed between the enzyme and DNA, preventing religation and producing double-stranded breaks that trigger apoptosis. Option C describes intercalating agents such as doxorubicin, though doxorubicin also targets topoisomerase II. Inhibition of topoisomerase I is the mechanism of camptothecins like irinotecan. Free radical mediated damage is typical of anthracyclines and bleomycin, not etiposide class podophyllotoxins.

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

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