Skarsgard L D, Vinczan A, Skwarchuk M W, Chaplin D J
Department of Medical Biophysics, B.C. Cancer Research Centre, Vancouver, Canada.
Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):363-7. doi: 10.1016/0360-3016(94)90290-9.
We examined the effect of acidic pH and hypoxia on the cytotoxicity of SR4233 and mitomycin C in vitro.
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.
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 approximately 2). In HT-29 cells, neither low pH nor hypoxia had any significant effect on mitomycin C toxicity.
Low pH, like hypoxia, is a common feature of solid tumors and can be an important determinant of the cytotoxic effect of bioreductive drugs such as SR4233 and mitomycin C.
我们在体外研究了酸性pH值和缺氧对SR4233和丝裂霉素C细胞毒性的影响。
肿瘤微环境对实体瘤细胞毒性治疗反应的重要性已得到充分证实。生物还原药物SR4233对缺氧细胞具有非常显著的选择性毒性。我们使用中国仓鼠和人类肿瘤细胞来研究低pH值和缺氧对培养细胞对SR4233或丝裂霉素C治疗反应的影响。
我们发现低pH值（6.6）对SR4233的缺氧毒性影响很小；然而，在有氧条件下，低pH值显著增加了1小时暴露于SR4233的细胞毒性作用，在V79和HT - 29细胞中的药物剂量增强率（ER）分别为3.9和2.5。在对丝裂霉素C的类似研究中，缺氧对V79细胞中丝裂霉素C的细胞毒性影响很小，尽管pH值为6.6在有氧和缺氧条件下均增强了细胞毒性（ER约为2）。在HT - 29细胞中，低pH值和缺氧对丝裂霉素C的毒性均无显著影响。
低pH值与缺氧一样，是实体瘤的一个共同特征，并且可能是生物还原药物如SR4233和丝裂霉素C细胞毒性作用的重要决定因素。
