Effect of oxygen on misonidazole chemosensitization and cytotoxicity in vitro

In order to assess the effect of oxygen on chemopotentiation by misonidazole (MISO), EMT-6/Ro tumor cells were exposed in vitro to combinations of CCNU and 1.0 mM MISO in culture medium equilibrated at various oxygen concentrations. The effect of oxygen on MISO cytotoxicity was similarly determined and compared with the relationship obtained for chemosensitization. MISO cytotoxicity and chemopotentiation were both oxygen sensitive, being maximal under anoxic conditions. Furthermore, the pattern of oxygen sensitivity was virtually identical for the two activities. These results suggest that a similar metabolic pathway, i.e., the oxygen-sensitive reduction of MISO to the nitroradical anion by cellular nitroreductases, is involved in the mechanism of both activities. The data further indicate that chemopotentiation can be expressed in cells treated at intermediate oxygen tensions. The implications of these findings with respect to the magnitude of chemopotentiation in vivo and the enhancement of normal tissue damage in animals treated with MISO and chemotherapy agents is discussed.