Mistry P, Loh S Y, Kelland L R, Harrap K R
Institute of Cancer Research, Sutton, Surrey, UK.
Int J Cancer. 1993 Nov 11;55(5):848-56. doi: 10.1002/ijc.2910550526.
Glutathione (GSH) has often been implicated in the mechanism of resistance to platinum anti-cancer drugs. It has been suggested that GSH may reduce the cytotoxicity of these drugs by forming inactive conjugates and by enhancing the repair of DNA-platinum crosslinks. In the present study we have examined the effect of D,L-buthionine-S,R-sulfoximine (BSO) pretreatment on the accumulation of platinum in a sensitive (CHI) and 2 relatively resistant (SKOV-3, HX/62) human ovarian-carcinoma cell lines following exposure to PtII- (cisplatin, carboplatin) and PtIV-drugs (tetraplatin). The metabolism of cisplatin and tetraplatin (particularly the extent of platinum-GSH conjugate formation) in the presence and absence of BSO pre-treatment was also examined in these cell lines. BSO pre-treatment reduced the accumulation of PtII but not that of PtIV drugs in the relatively resistant SKOV-3 and HX/62 cell lines. It had no effect on the accumulation of either class of drugs in the sensitive CHI cells. Metabolism studies with cisplatin showed that the SKOV-3 and HX/62 cells, which contained 2- to 3-fold higher levels of GSH, were able to inactivate a greater proportion of cellular cisplatin, by the formation of platinum-GSH conjugates, than the CHI cells. A significant inhibition in formation of these conjugates, by BSO-induced depletion of cellular GSH (over 80%), did not, however, increase cisplatin concentration in the resistant cells. In contrast, a small increase in cisplatin concentration was observed in the sensitive cells following BSO pre-treatment. Comparison of cisplatin and tetraplatin metabolism in the SKOV-3 cells indicated that a greater proportion of the latter drug was inactivated by formation of GSH conjugates. BSO-induced depletion of cellular GSH in this cell line significantly reduced the formation of such conjugates from both drugs. However, concomitant increases in intracellular levels of reactive species were observed only after tetraplatin exposure. Our data suggest that the greater potentiation of PtIV- compared with PtII-drug cytotoxicity in the relatively resistant cell lines following 24 hr BSO pre-treatment may be caused by a differential effect of BSO on the metabolism and cellular distribution of these drugs. A BSO-induced reduction in PtII- but not PtIV-drug accumulation in these cells may also partially contribute to the differential potentiation of cytotoxicity of these drugs.
谷胱甘肽（GSH）常常与对铂类抗癌药物的耐药机制有关。有人提出，GSH可能通过形成无活性的结合物以及增强DNA - 铂交联的修复来降低这些药物的细胞毒性。在本研究中，我们检测了D，L - 丁硫氨酸 - S，R - 亚砜亚胺（BSO）预处理对人卵巢癌细胞系（敏感细胞系CHI以及2个相对耐药的细胞系SKOV - 3、HX/62）在暴露于PtII类药物（顺铂、卡铂）和PtIV类药物（四铂）后铂蓄积的影响。还检测了在有或无BSO预处理的情况下，这些细胞系中顺铂和四铂的代谢情况（尤其是铂 - GSH结合物的形成程度）。BSO预处理降低了相对耐药的SKOV - 3和HX/62细胞系中PtII类药物的蓄积，但未降低PtIV类药物的蓄积。它对敏感的CHI细胞中这两类药物的蓄积均无影响。顺铂的代谢研究表明，SKOV - 3和HX/62细胞中GSH水平比CHI细胞高2至3倍，通过形成铂 - GSH结合物，它们能够使细胞内更大比例的顺铂失活。然而，BSO诱导细胞内GSH耗竭（超过80%）导致这些结合物形成受到显著抑制，这并未增加耐药细胞中顺铂的浓度。相反，BSO预处理后，敏感细胞中顺铂浓度出现小幅增加。SKOV - 3细胞中顺铂和四铂代谢的比较表明，后者药物通过形成GSH结合物而失活的比例更大。该细胞系中BSO诱导的细胞内GSH耗竭显著减少了这两种药物形成此类结合物的情况。然而，仅在暴露于四铂后才观察到细胞内活性物质水平的相应增加。我们的数据表明，在24小时BSO预处理后，相对耐药细胞系中PtIV类药物的细胞毒性比PtII类药物增强得更多，这可能是由于BSO对这些药物的代谢和细胞分布有不同影响所致。BSO诱导这些细胞中PtII类药物而非PtIV类药物蓄积减少，这也可能部分导致了这些药物细胞毒性增强的差异。
