Xia H, Pinto T, Hu X, Benson P J, Zaren H A, Gupta V, Singh S
Cancer Research Laboratory, Mercy Cancer Institute, Pittsburgh, Pennsylvania 15219, USA.
Cancer Res. 1996 Aug 1;56(15):3495-8.
Recent studies, using a cell-free system, have suggested that thiol-dependent nonenzymatic bioactivation may be responsible for the superior antitumor activity of the mitomycin C analogue BMS-181174 [N-7-[2-(4-nitrophenyldithio)ethyl]mitomycin C] when compared to the parent compound. If operational in tumor cells, this pathway could have enormous clinical implications since tumor cell resistance to a variety of anticancer agents is often associated with increased glutathione (GSH) levels and BMS-181174 may be used to reverse this mechanism of resistance. The present study was undertaken to determine the role of GSH in cellular activation of BMS-181174 using a pair of well-characterized human bladder cancer cells (J82 and SCaBER) as a model. A 20-h pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused about 80-88% reduction in cellular GSH levels. Surprisingly, the sensitivity of both cells to BMS-181174 was increased, not reduced, by BSO-induced GSH depletion. On the other hand, the cytotoxicity of BMS-181174 was significantly reduced in both cells by a 4-h pretreatment with 1 mM GSH. Like BSO, a 4-h pretreatment with another thiol compound (cysteine) resulted in a statistically significant sensitization of both cells to BMS-181174. Cellular GSH levels were not affected in either of the cell lines by pretreatment with GSH or cysteine. In conclusion, the results or the present study argue against a role of GSH in cellular nonenzymatic activation of BMS-181174 in J82 and SCaBER cells.
最近使用无细胞系统进行的研究表明，与母体化合物相比，硫醇依赖性非酶生物活化可能是丝裂霉素C类似物BMS-181174 [N-7-[2-(4-硝基苯基二硫基)乙基]丝裂霉素C]具有卓越抗肿瘤活性的原因。如果该途径在肿瘤细胞中起作用，那么它可能具有重大的临床意义，因为肿瘤细胞对多种抗癌药物的耐药性通常与谷胱甘肽（GSH）水平升高有关，而BMS-181174可用于逆转这种耐药机制。本研究旨在以一对特征明确的人膀胱癌细胞（J82和SCaBER）为模型，确定GSH在BMS-181174细胞活化中的作用。用无毒浓度的D,L-丁硫氨酸-S,R-亚砜亚胺（BSO）对J82和SCaBER细胞进行20小时预处理，可使细胞内GSH水平降低约80-88%。令人惊讶的是，BSO诱导的GSH耗竭增加了两种细胞对BMS-181174的敏感性，而非降低。另一方面，用1 mM GSH对两种细胞进行4小时预处理，可显著降低BMS-181174的细胞毒性。与BSO一样，用另一种硫醇化合物（半胱氨酸）进行4小时预处理，可使两种细胞对BMS-181174的敏感性在统计学上显著增加。用GSH或半胱氨酸预处理均未影响两种细胞系中的细胞GSH水平。总之，本研究结果表明GSH在J82和SCaBER细胞中对BMS-181174的细胞非酶活化过程中不起作用。
