HIGH-RESISTANCE TO CISPLATIN IN HUMAN OVARIAN-CANCER CELL-LINES IS ASSOCIATED WITH MARKED INCREASE OF GLUTATHIONE SYNTHESIS
HIGH-RESISTANCE TO CISPLATIN IN HUMAN OVARIAN-CANCER CELL-LINES IS ASSOCIATED WITH MARKED INCREASE OF GLUTATHIONE SYNTHESIS
复制标题
DOI：
10.1073/pnas.89.7.3070
复制
发表时间：
1992-04-01
影响因子：
11.1
通讯作者：
ANDERSON, ME
中科院分区：
文献类型：
--
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
人卵巢肿瘤细胞系暴露于顺铂导致细胞系的发展，表现出越来越多的耐药性，这是密切相关的细胞谷胱甘肽水平的增加。 获得的细胞系显示出30- 1000倍的抗性增加;这些细胞与原始药物敏感细胞相比，谷胱甘肽水平也显著增加（13- 50倍）。 这些水平的耐药顺铂和细胞谷胱甘肽水平大大高于以前的报道。 非常高的顺铂耐药性与γ-谷氨酰半胱氨酸合成酶和γ-谷氨酰转肽酶的mRNA表达增强相关;免疫印迹显示γ-谷氨酰半胱氨酸合成酶增加，但谷胱甘肽合成酶未增加。 谷胱甘肽S-转移酶活性不受影响，确定与氯二硝基苯作为底物。 这些研究表明，检查谷胱甘肽合成的调节作为临床预后的指标的潜在价值。 高耐药细胞系被证明可用于研究肿瘤细胞获得药物和辐射抗性的多种机制。
Exposure of human ovarian tumor cell lines to cisplatin led to development of cell lines that exhibited increasing degrees of drug resistance, which were closely correlated with increase of the levels of cellular glutathione. Cell lines were obtained that showed 30- to 1000-fold increases in resistance; these cells also had strikingly increased (13- to 50-fold) levels of glutathione as compared with the drug-sensitive cells of origin. These levels of resistance to cisplatin and the cellular glutathione levels are substantially greater than previously reported. Very high cisplatin resistance was associated with enhanced expression of mRNAs for gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase; immunoblots showed increase of gamma-glutamylcysteine synthetase but not of glutathione synthetase. Glutathione S-transferase activity was unaffected, as determined with chlorodinitrobenzene as a substrate. These studies suggest the potential value of examining regulation of glutathione synthesis as an indicator of clinical prognosis. The highly resistant cell lines are proving useful for studying the multiple mechanisms by which tumor cells acquire drug- and radiation-resistance.