KeywordsCancer; Cisplatin; DNA damage; Low-energy electrons; OxaliplatinThe sensitization of malignant cells to ionizing radiation is the clinical rationale for the use of platinum-based concurrent chemoradiotherapy (CCRT) for cancer treatment; however, the specific mechanisms of radiosensitization and their respective contributions still remain unknown [1] . Biological mechanisms such as inhibition of DNA repair may contribute to the efficacy of CCRT [2] ; nevertheless, there is a dearth of information on the possible contribution of nanoscopic mechanisms to the generation of lethal DNA lesions such as double-strand breaks (DSB). The present study demonstrates that the abundant near zero-eV (0.5-eV) electrons, created by ionizing radiation during radiotherapy, induce DSB in supercoiled plasmid DNA modified by platinum anticancer drugs (Pt-drugs), but not in unmodified DNA. They do so more efficiently than other types of radiation, including soft X-rays and 10-eV electrons. The formation of DSB by 0.5-eV electrons is found to be a single-hit process. These findings reveal insights into the radiosensitization mechanism of Pt-drugs that can have implications for the development of optimal clinical protocols for platinum-based CCRT and the deployment of in-situ sources of subexcitation-energy electrons (e.g., Auger-electron emitting radionuclides) to efficiently enhance DSB formation in DNA modified by Pt-drugs in malignant cells.Pt-drug molecules react with cellular components, including DNA, RNA and proteins, via ligand exchange at the platinum atom [3] . Binding of Pt-drugs to DNA causes a local distortion of the DNA conformation affecting the physical and chemical properties of the molecule, particularly at the site of platination [4] . These modifications are believed to enhance the effects of radiation on the modified DNA by perturbing processes occurring during the physical and chemical stages of the interaction of radiation with DNA [5] . In an aqueous solution of DNA, cisplatin enhances the formation of DNA strand breaks by the reaction of both hydroxyl radicals and hydrated electrons at the site of platination through
CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript the increased accessibility of these species to sugar moieties and dissociative electron transfer [6] . Additionally, in the presence of Pt-DNA adducts, low energy electrons (LEEs, i.e., electrons of 0-30 eV) have a higher cross section for DNA damage than other types of radiations [7,8] . Previously, we hypothesized that at such energies, an incident electron is captured by a DNA constituent at the platination site to form a local transient negative ion (TNI) via a resonance process, which may subsequently rupture chemical bonds via either dissociative electron attachment (DEA) or dissociative electronic excitation (DEE) [8,9] . To determine the primary mechanism responsible for the enhanced damage to DNA modified by Pt-drugs, in the present study, we investigated the contribution and efficiency of these decay channels in ...