The use of nitroaromatic compounds as hypoxic cell radiosensitizers

This paper describes the chemical basis for the use of nitroaromatic compounds as hypoxic radiosensitizers. The biological and chemical properties suitable for the quantitative investigation of structure-activity relationships are discussed. Radiosensitization of hypoxic mammalian cells in vitro is a suitable test system if due regard is taken of the temperature and the concentration/time profile of the drug in extrapolating the results to the situation in vivo. The reduction chemistry of nitroaromatic compounds is summarized, with emphasis on the implications in their metabolism and toxicology, and on the similarities between the selectivity of nitroaromatic compounds against anaerobic micro-organisms and both the differential toxicity towards hypoxic cells and the absence of radiosensitization of oxic cells. The redox properties of nitroaromatic compounds are important in determining the radiosensitization efficiency and cytotoxicity. The one-electron reduction potentials of the compounds have been shown to be a suitable chemical parameter for use in structure-activity relationships, although the use of other measures of redox properties are also considered, including Hammett constants, electron spin resonance hyperfine interactions and polarographic half-wave potentials. The effects of redox properties on both rates and equilibria in chemical reactions are discussed, and the implications of a theory of electron-transfer reactions considered. Both radiosensitization and the purely chemotherapeutic effects of nitroaromatic compounds against hypoxic cells have to be considered in developing a model for optimizing a clinically useful radiosensitizer. Lipophilicity is much less important in vitro than it is likely to be in vivo. (Auth.)