Ubiquitous induction of resistance to platinum drugs in human ovarian, cervical, germ-cell and lung carcinoma tumor cells overexpressing isoforms 1 and 2 of dihydrodiol dehydrogenase
Ubiquitous induction of resistance to platinum drugs in human ovarian, cervical, germ-cell and lung carcinoma tumor cells overexpressing isoforms 1 and 2 of dihydrodiol dehydrogenase
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DOI：
10.1007/s00280-004-0815-0
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发表时间：
2004-10-01
影响因子：
3
通讯作者：
Simpkins, H
中科院分区：
文献类型：
--
作者：
Deng, HB;Adikari, M;Simpkins, H
我们最近发现，在人卵巢癌细胞（2008/C13*）中，二氢二醇脱氢酶（DDH）的过度表达与顺铂和卡铂耐药相关。此外，我们还阐明了用全长DDH 1 cDNA转染亲代人卵巢癌细胞导致诱导对铂类药物的耐药性。转染细胞中顺铂抗性的发展与DDH酶活性的增加相关。以前的研究已经确定了几种不同的顺铂耐药机制，包括改变DNA修复能力，增加GSH为基础的解毒，增加金属硫蛋白含量。然而，这些机制中没有一个被发现与来自不同组织来源的肿瘤细胞中顺铂耐药性的发展普遍相关。本研究旨在评估DDH 1或DDH 2的过表达（在人卵巢、宫颈、肺和生殖细胞肿瘤细胞系中）是否能特异性诱导这些细胞系对铂类药物的耐药性。我们证明了DDH 1或DDH 2表达增加（通过转染克隆中酶活性增加来判断）与顺铂和卡铂耐药性的发展存在普遍关联。此外，我们还发现对具有不同作用模式的抗癌药物（包括紫杉醇、长春新碱、盐酸多柔比星和美法仑）缺乏交叉耐药性。虽然目前还不清楚DDH是如何参与铂类药物耐药性，该基因作为一个致病因素，在一系列的细胞系来自不同的肿瘤细胞内的组成不同，表明破译这一迄今尚未确定的途径，可以产生耐药性铂类药物的重要性。
We have recently demonstrated that overexpression of dihydrodiol dehydrogenase (DDH) in human ovarian carcinoma cells (2008/C13*) is associated with cisplatin and carboplatin resistance. Furthermore, we have also elucidated that transfection of parental human ovarian carcinoma cells with a full-length DDH1 cDNA leads to induction of resistance to the platinum drugs. The development of cisplatin resistance in the transfected cells is associated with an increase in DDH enzyme activity. Previous studies have identified several different mechanisms for development of cisplatin resistance, including altered DNA repair capacity, increased GSH-based detoxification, and increased metallothionein content. However, none of these mechanisms has been found to be universally associated with the development of cisplatin resistance in tumor cells from different tissue sources. The present study was undertaken to assess whether overexpression of DDH1 or DDH2 (in human ovarian, cervical, lung and germ-cell tumor cell lines) could specifically induce resistance to the platinum drugs in these cell lines. We demonstrated a ubiquitous association of increased expression of DDH1 or DDH2 (as judged by increased enzyme activity in transfected clones) with development of resistance to cisplatin and carboplatin. Moreover, we also found a lack of cross-resistance to anticancer drugs that have a different mode of action including paclitaxel, vincristine, doxorubicin hydrochloride, and melphalan. Although at present it is not clear how DDH is involved in platinum drug resistance, the identification of this gene as a causal factor in a series of cell lines derived from different tumors with different intracellular compositions indicates the importance of deciphering this hitherto undefined pathway which can produce resistance to platinum drugs.