Cisplatin and adriamycin resistance are associated with MutL alpha and mismatch repair deficiency in an ovarian tumor cell line
Cisplatin and adriamycin resistance are associated with MutL alpha and mismatch repair deficiency in an ovarian tumor cell line
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DOI：
10.1074/jbc.271.33.19645
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发表时间：
1996-08-16
影响因子：
4.8
通讯作者：
Modrich, P
中科院分区：
文献类型：
--
作者：
Drummond, JT;Anthoney, A;Modrich, P
与亲代A2780卵巢肿瘤细胞相比，一种耐阿霉素和两种独立的顺式二胺二氯铂（II）耐药衍生物的提取物在链特异性错配修复中存在缺陷。三种超可变耐药细胞系的修复缺陷仅在引导反应的链断裂位于错配的3'处时才明显，并且在每种情况下，通过添加纯化的MutL α异二聚体将修复恢复到提取物中。通过免疫学试验判断，耐药与MutL α MLH1亚基的缺失和PMS2亚基水平的大幅降低有关。这些发现暗示在这些抗肿瘤药物的细胞毒性作用中存在功能性错配修复系统，并可能对其临床应用产生影响。
In contrast to parental A2780 ovarian tumor cells, extracts of one doxorubicin-resistant and two independent cis-diamminedichloroplatinum(II)-resistant derivatives are defective in strand-specific mismatch repair. The repair defect of the three hypermutable, drug-resistant cell lines is only evident when the strand break that directs the reaction is located 3' to the mismatch, and in each case repair is restored to extracts by addition of purified MutL alpha heterodimer. As judged by immunological assay, drug resistance is associated with the virtual absence of the MutL alpha MLH1 subunit and greatly reduced levels of the PMS2 subunit. These findings implicate a functional mismatch repair system in the cytotoxic effects of these antitumor drugs and may have ramifications for their clinical application.