The Physico‐Chemical Basis of DNA Radiosensitization: Implications for Cancer Radiation Therapy

High‐energy radiation is used in combination with radiosensitizing therapeutics to treat cancer. The most common radiosensitizers are halogenated nucleosides and cisplatin derivatives, and recently also metal nanoparticles have been suggested as potential radiosensitizing agents. The radiosensitizing action of these compounds can at least partly be ascribed to an enhanced reactivity towards secondary low‐energy electrons generated along the radiation track of the high‐energy primary radiation, or to an additional emission of secondary reactive electrons close to the tumor tissue. This is referred to as physico‐chemical radiosensitization. In this Concept article we present current experimental methods used to study fundamental processes of physico‐chemical radiosensitization and discuss the most relevant classes of radiosensitizers. Open questions in the current discussions are identified and future directions outlined, which can lead to optimized treatment protocols or even novel therapeutic concepts. The concept of physico‐chemical radiosensitization is based the enhanced reactivity of DNA towards secondary low‐energy electrons, or the increase of local concentration of such electrons. This can for example be achieved by incorporation of halogenated nucleosides into DNA, or by administration of metal nanoparticles. Fundamental mechanisms of low‐energy electron‐induced DNA damage are discussed and recent experimental advancements in the quantification of DNA strand breaks in chemically modified DNA are presented.