THE INFLUENCE OF HYPOXIA ON THE CYTOTOXICITY OF CONCOMITANT KW-2149 AND IONIZING IRRADIATION IN CHINESE-HAMSTER FIBROBLASTS

ma-L-glutamylamino)ethyl)dithio)ethyl))-mito-mycin C (KW-2149) is a ne wly synthesized water-soluble mitomycin C (MMC) analog. Preclinical te sting showed an interesting activity profile and a superior hematologi cal tolerance in murine models. The aim of this study was to investiga te the interaction of this compound with ionizing radiation, both unde r normoxic and hypoxic conditions, in Chinese hamster fibroblasts (V79 ). V79 cells were irradiated both under normoxic conditions and after a 1 h period of hypoxia. Paired irradiation dose-response the signific ance of radioresistance under hypoxia with an oxygen enhancement ratio of approximately 3. In contrast to MMC, KW-2149 showed no increased c ytotoxic effect on hypoxic V79 cells. The cytotoxic effect of KW-2149 increased with increasing concentration, irrespective of the ambient o xygen pressure. When KW-2149 was combined with irradiation under hypox ic conditions, cytotoxicity was significantly enhanced under these con ditions. The difference in survival between normoxic and hypoxic condi tions was statistically significant (p<0.004). These data suggest a ra diosensitizing effect of KW-2149, more pronounced under hypoxic condit ions. This effect increases with radiation dose. It also corroborates earlier suggestions of a different mode of action of KW-2149 as compar ed to MMC.