DNA mismatch repair and acquired cisplatin resistance in E-coli and human ovarian carcinoma cells
DNA mismatch repair and acquired cisplatin resistance in E-coli and human ovarian carcinoma cells
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DOI：
10.1016/s1568-7864(02)00187-8
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发表时间：
2003-01-02
期刊：
影响因子：
3.8
通讯作者：
Karran, P
中科院分区：
文献类型：
--
作者：
Massey, A;Offman, J;Karran, P
在两个模型系统：大肠杆菌darn突变体和A2780卵巢癌细胞系中，已经研究了有缺陷的DNA错配修复（MMR）对顺二氨二氯铂（II）（顺铂）获得性耐药的作用。在顺铂处理的darn突变体的存活者中，经常观察到MMR失活——这表现为获得升高的自发突变体表型。这些存活者对进一步的顺铂治疗表现出稳定的耐药性。相反，在12个经顺铂暴露后存活并获得稳定耐药性的A2780独立克隆中，没有一个是修复缺陷的。没有一个表现出与MMR缺陷相关的标志性甲基化耐受表型，在所有12个变体中都很容易检测到编码5种MMR蛋白的mRNA，并且4种关键MMR蛋白的水平与修复正常的亲本细胞中的水平相似。进一步的分析表明A2780中存在两种不同的获得性耐药机制。第一种是一种保护作用，它降低了DNA铂化的水平。第二种表现为顺铂处理后对细胞周期阻滞的敏感性降低，以及随之而来的细胞凋亡减少。数据表明，尽管MMR的缺失是darn细菌中获得性耐药的一个重要机制，但在人类细胞中，与DNA保护或药物损伤后细胞周期进程相关的改变似乎比MMR的废除作为耐药调节剂更有可能。（C）2002 Elsevier Science B.V.保留所有权利。
The contribution of defective DNA mismatch repair (MMR) to acquired resistance to cis-diamminedichloroplatinum(II) (cisplatin) has been investigated in two model systems: E coli darn mutants and the A2780 ovarian carcinoma cell line. Inactivation of MMR-as indicated by the acquisition of an elevated spontaneous mutator phenotype-was observed frequently among survivors of cisplatin-treated darn mutants. These survivors exhibited a stable resistance to further cisplatin treatment. In contrast, none of twelve independent clones of A2780 that had survived cisplatin exposure and acquired stable drug resistance were repair defective. None exhibited the hallmark methylation tolerant phenotype associated with a MMR defect, mRNAs encoding five MMR proteins were easily detectable in all twelve variants, and the levels of four key MMR proteins were similar to those in the repair proficient parental cells. Further analysis indicated two different mechanisms of acquired resistance in A2780. The first was a protective effect that reduced the level of DNA platination. The second was observed as a reduced sensitivity to cell cycle arrest after cisplatin treatment and a consequent reduced apoptosis. The data suggest that although loss of MMR is a significant mechanism of acquired drug resistance in darn bacteria, alterations related to DNA protection or cell cycle progression after drug damage appear to be more probable than abrogation of MMR as resistance modulators in human cells. (C) 2002 Elsevier Science B.V. All rights reserved.