Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells.
Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells.
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DOI：
10.1038/sj.bjc.6602447
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发表时间：
2005-03-28
影响因子：
8.8
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中科院分区：
文献类型：
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由于内在或获得性耐药性，基于铂的化疗方案最终不成功。了解铂类药物敏感性/耐药性的分子基础对于新药和治疗方案的开发是必要的。为了确定这些决定因素，我们使用 cDNA 微阵列筛选评估了一组 14 个不相关的人卵巢癌细胞系中约 4000 个基因的表达，这些细胞系来自未经治疗或接受铂类化疗的患者。对这些数据进行了相对于细胞对四种铂类药物（顺式二氨二氯铂（顺铂）、卡铂、DACH-（草酸）铂（II）（奥沙利铂）和顺式二氨二氯（2-甲基吡啶）铂（II）（AMD473））的敏感性以及细胞增殖率的分析。微阵列数据与药物敏感性和耐药性的相关分析揭示了 Stat1 表达与顺铂 (r=0.65) 和 AMD473 (r=0.76) 敏感性降低之间的显着相关性。这些结果通过定量 RT-PCR 和蛋白质印迹分析得到证实。为了研究这些发现的功能意义，将全长 Stat1 cDNA 转染到药物敏感的 A2780 人卵巢癌细胞中。与亲本细胞相比，所得的 Stat1 表达增加的克隆对顺铂和 AMD473 的耐药性高出三到五倍。使用 Janus 激酶抑制剂 AG490 研究了抑制 Jak/Stat 信号传导对铂类药物敏感性的影响。用 AG490 预处理铂耐药细胞会显着增加对 AMD473 的敏感性，但不会显着增加对顺铂或奥沙利铂的敏感性。总体而言，结果表明 cDNA 微阵列分析可成功用于识别药物敏感性/耐药性的决定因素，并且对该数据库中其他候选基因的未来功能研究可能会加深对耐药表型的了解。
Platinum-based chemotherapeutic regimens are ultimately unsuccessful due to intrinsic or acquired drug resistance. Understanding the molecular basis for platinum drug sensitivity/resistance is necessary for the development of new drugs and therapeutic regimens. In an effort to identify such determinants, we evaluated the expression of approximately 4000 genes using cDNA microarray screening in a panel of 14 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy. These data were analysed relative to the sensitivities of the cells to four platinum drugs (cis-diamminedichloroplatinum (cisplatin), carboplatin, DACH-(oxalato)platinum (II) (oxaliplatin) and cis-diamminedichloro (2-methylpyridine) platinum (II) (AMD473)) as well as the proliferation rate of the cells. Correlation analysis of the microarray data with respect to drug sensitivity and resistance revealed a significant association of Stat1 expression with decreased sensitivity to cisplatin (r=0.65) and AMD473 (r=0.76). These results were confirmed by quantitative RT–PCR and Western blot analyses. To study the functional significance of these findings, the full-length Stat1 cDNA was transfected into drug-sensitive A2780 human ovarian cancer cells. The resulting clones that exhibited increased Stat1 expression were three- to five-fold resistant to cisplatin and AMD473 as compared to the parental cells. The effect of inhibiting Jak/Stat signalling on platinum drug sensitivity was investigated using the Janus kinase inhibitor, AG490. Pretreatment of platinum-resistant cells with AG490 resulted in significant increased sensitivity to AMD473, but not to cisplatin or oxaliplatin. Overall, the results indicate that cDNA microarray analysis may be used successfully to identify determinants of drug sensitivity/resistance and future functional studies of other candidate genes from this database may lead to an increased understanding of the drug resistance phenotype.
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影响因子：
8.4
作者：
PEREZ, RP;GODWIN, AK;HAMILTON, TC
通讯作者：
HAMILTON, TC
影响因子：
30.8
作者：
Ross, DT;Scherf, U;Brown, PO
通讯作者：
Brown, PO
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
6.5
作者：
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通讯作者：
Klein, B
影响因子：
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作者：
HILL, SM;RODGERS, CS;WILSON, AP
通讯作者：
WILSON, AP