The relationship of SR-2508 sensitizer enhancement ratio to cellular glutathione levels in human tumor cell lines.

We have recently demonstrated that intracellular elevation of glutathione (GSH) by oxothiazolidine 4-carboxylate lessens SR-2508 hypoxic cell radiosensitization in Chinese hamster cells. This observation, coupled with the fact that GSH depletion potentiates SR-2508 hypoxic radiosensitization, prompted a study of human tumor cell lines whose inherent GSH levels are high compared to normal human cell lines or rodent cell lines. Sensitizer enhancement ratios (SER) for a range of SR-2508 concentrations were determined for human tumor cell lines varying in inherent GSH levels. The SER (at the 1% survival level) for 1 mM SR-2508 was found to decrease as the inherent intracellular GSH level increased, particularly for clinically relevant SR-2508 concentrations. All human tumor cell lines studied yielded lower SER values than Chinese hamster V79 cells over the SR-2508 concentrations studied. GSH depletion by buthionine sulfoximine (BSO) of a human tumor line (A549) particularly high in GSH resulted in potentiation of SR-2508 effects. Maximal sensitization occurred when extremely low GSH levels were attained; however, enhancement was observed for a drop of only 30% in GSH levels. Should these high GSH levels seen in human tumor cell lines also apply to clonogenic or potentially clonogenic cells in human tumors in vivo, these findings might explain, in part, the negative results of some human nitroimidazole clinical trials.