Electron-Induced Fragmentation of 5-Iodouridine: Implications for Enhanced Radiotherapy

5-Iodouridine is a known and potentially efficient radiosensitizer; however, it has not been considered for clinical use because of its poor metabolic incorporation into DNA. Recent development of a novel pro-drug, ropidoxuridine, has improved the bioavailability of this halogenated nucleoside, although the exact mechanism of its radiosensitizing action remains not fully elucidated. Here, we demonstrate that low-energy electrons─abundantly generated along radiation tracks─efficiently dissociate the halogenated nucleoside via the primary pathway (99%), producing an iodine anion and a uridine-yl^• neutral radical, with a high approximate DEA cross section of (2.7 ± 1.9)×10^-14 cm². The latter, known to be highly reactive, subsequently induces hydrogen abstraction, leading to DNA strand breaks. The damage induced in 5IUrd by low-energy electrons is found to be about 700 times greater than that in thymidine and about 4 times that of the clinically used 5-fluorouridine. These findings may contribute to the development of future cancer therapy strategies by synergistically combining 5IUrd with cisplatin or gold nanoparticles, which act as a source of secondary low-energy electrons during radiation therapy.