THE EFFECT OF LOW PH AND HYPOXIA ON THE CYTOTOXIC EFFECTS OF SR4233 AND MITOMYCIN-C IN-VITRO

Purpose: We examined the effect of acidic pH and hypoxia on the cytoto xicity of SR4233 and mitomycin C in vitro. Methods and Materials: The importance of tumor microenvironment to the response of solid tumors t o cytotoxic treatment is well established. The bioreductive drug SR423 3 has a very substantial selective toxicity for hypoxic cells. We have used both Chinese hamster and human tumor cells to investigate the in fluence of low pH and hypoxia on the response of cultured cells to tre atment with SR4233 or mitomycin C. Results: We found that low pH (6.6) had little effect on the hypoxic toxicity of SR4233; under aerobic co nditions, however, low pH substantially increased the cytotoxic effect s of 1 h exposure to SR4233, with drug dose enhancement ratios (ER) of 3.9 and 2.5 in V79 and BT-29 cells, respectively. In similar studies with mitomycin C, hypoxia had little effect on the cytotoxicity of mit omycin C in V79 cells, though a low pH of 6.6 enhanced the cytotoxicit y under both aerobic and hypoxic conditions (ER similar to 2). In HT-2 9 cells, neither low pH nor hypoxia had any significant effect on mito mycin C toxicity. Conclusion: Low pH, like hypoxia, is a common featur e of solid tumors and can be an important determinant of the cytotoxic effect of bioredutive drugs such as SR4233 and mitomycin C.