In the management of locally advanced cervical cancer (Stage IIB-IVA), the addition of concurrent cisplatin to external beam radiotherapy followed by brachytherapy is supported by multiple randomized trials. What is the proposed mechanism of cisplatin radiosensitization?

• A Cisplatin chelates calcium in G2/M checkpoint kinases, arresting cells in most radiosensitive phase
• B Cisplatin depletes glutathione in tumor cells, removing the main antioxidant protecting against radiation free radicals
• C Cisplatin forms intrastrand and interstrand DNA crosslinks that inhibit repair of radiation-induced DNA double-strand breaks ✓
• D Cisplatin blocks topoisomerase II, preventing rejoining of radiation-induced DNA strand breaks

Explanation

Cisplatin acts as a radiosensitizer primarily by forming platinum-DNA adducts (intrastrand crosslinks between adjacent purines, especially GG and AG) that inhibit the nucleotide excision repair (NER) pathway. Since radiation kills cells primarily by creating DNA double-strand breaks that require homologous recombination and NER for repair, cisplatin-adducted DNA cannot be efficiently repaired, leading to enhanced cytotoxicity. Additionally, cisplatin may cause cell cycle arrest at S/G2, when cells are relatively radiosensitive. Glutathione depletion and topoisomerase II inhibition are mechanisms of other agents.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

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