Smith Judith A, Gaikwad Anjali, Ramondetta Lois M, Wolf Judith K, Brown Jubilee
Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA.
Gynecol Oncol. 2006 Nov;103(2):518-22. doi: 10.1016/j.ygyno.2006.03.042. Epub 2006 May 9.
The primary objective of this study was to determine the mechanism(s) of cisplatin drug resistance in endometrial cancer cell lines. To evaluate the mechanism that gemcitabine modulates cisplatin drug resistance in endometrial cancer cell lines.
Combination treatment was completed in panel of four human endometrial cancer cell lines. Growth inhibition assays were conducted in each cell line evaluating combinations of the Ic25, Ic50, and Ic90 to determine optimal dosing for the combination of gemcitabine plus cisplatin. Evaluation of the correlative biological targets for modulation of platinum drug resistance was completed by the respective immunohistochemistry assays.
Downregulation of glutathione-S-transferase (GST) activity by 11% to 100% was observed with an associated 78.6% to 100% decrease in intracellular glutathione (GSH) concentrations. In the gemcitabine plus cisplatin treatment arm compared to either alone, there was also downregulation of MSH2, p53, and ERCC1 expression. No changes observed in the pro-apoptotic proteins, BAX or BAD, expression, AKT activation, or MDR1/PGP expression regardless of treatment with combination of gemcitabine plus cisplatin or either agent alone.
There is likely more than one mechanism contributing to the increase synergistic in vitro platinum-resistant cell lines and increase clinical activity that has been observed in patients with platinum-resistant tumors. In this in vitro study, we determined the downregulation of intracellular GST activity and GSH concentration were the predominant mechanisms involved in the modulation of platinum resistance. Downregulation of MSH2, p53 and ERCC1 expression may also contribute to increase cytotoxic activity compared to cisplatin alone.
本研究的主要目的是确定子宫内膜癌细胞系中顺铂耐药的机制。评估吉西他滨调节子宫内膜癌细胞系中顺铂耐药的机制。
在四种人子宫内膜癌细胞系中完成联合治疗。在每个细胞系中进行生长抑制试验，评估Ic25、Ic50和Ic90的组合，以确定吉西他滨加顺铂联合用药的最佳剂量。通过各自的免疫组织化学试验完成对铂类耐药调节相关生物学靶点的评估。
观察到谷胱甘肽-S-转移酶（GST）活性下调11%至100%，细胞内谷胱甘肽（GSH）浓度相应降低78.6%至100%。与单独使用吉西他滨或顺铂相比，在吉西他滨加顺铂治疗组中，MSH2、p53和ERCC1的表达也下调。无论使用吉西他滨加顺铂联合治疗还是单独使用任何一种药物，促凋亡蛋白BAX或BAD的表达、AKT激活或MDR1/PGP表达均未观察到变化。
可能有多种机制导致体外铂耐药细胞系的协同作用增加以及铂耐药肿瘤患者临床活性增加。在这项体外研究中，我们确定细胞内GST活性和GSH浓度的下调是铂耐药调节的主要机制。与单独使用顺铂相比，MSH2、p53和ERCC1表达的下调也可能有助于增加细胞毒性活性。
