The effect of low ph and hypoxia on the cytotoxic effects of SR4233 and mitomycin C in vitro

Abstract

Purpose : We examined the effect of acidic pH and hypoxia on the cytotoxicity of SR4233 and mitomycin C in vitro. Methods and Materials : The importance of tumor microenvironment to the response of solid tumors to cytotoxic treatment is well established. The bioreductive drug SR4233 has a very substantial selective toxicity for hypoxic cells. We have used both Chinese hamster and human tumor cells to investigate the influence of low pH and hypoxia on the response of cultured cells to treatment with SR4233 or mitomycin C. Results : We found that low pH (6.6) had little effect on the hypoxic toxicity of SR4233; under aerobic conditions, however, low pH substantially increased the cytotoxic effects of 1 h exposure to SR4233, with drug dose enhancement ratios (ER) of 3.9 and 2.5 in V79 and HT-29 cells, respectively. In similar studies with mitomycin C, hypoxia had little effect on the cytotoxicity of mitomycin C in V79 cells, though a low pH of 6.6 enhanced the cytotoxicity under both aerobic and hypoxic conditions (ER ∼ 2). In HT-29 cells, neither low pH nor hypoxia had any significant effect on mitomycin C toxicity. Conclusion : Low pH, like hypoxia, is a common feature of solid tumors and can be an important determinant of the cytotoxic effect of bioredutive drugs such as SR4233 and mitomycin C.