Fink D, Nebel S, Aebi S, Zheng H, Cenni B, Nehmé A, Christen R D, Howell S B
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla 92093-0058, USA.
Cancer Res. 1996 Nov 1;56(21):4881-6.
Loss of DNA mismatch repair occurs in many types of tumors. The effect of the loss of DNA mismatch repair activity on sensitivity to cisplatin and a panel of analogues was tested using two pairs of cell lines proficient or deficient in this function. HCT116+ch2, a human colon cancer cell line deficient in hMLH1, was 2.1-fold resistant to cisplatin and 1.3-fold resistant to carboplatin when compared to a subline complemented with chromosome 3 expressing a wild-type copy of hMLH1. Likewise, the human endometrial cancer cell line HEC59, which is deficient in hMSH2, was 1.8-fold resistant to cisplatin and 1.5-fold resistant to carboplatin when compared to a subline complemented with chromosome 2 with a wild-type hMSH2. In contrast to cisplatin and carboplatin, which form the same types of adducts in DNA, there was no difference in sensitivity between the DNA mismatch repair-proficient and -deficient cell lines for oxaliplatin, tetraplatin, transplatin, JM335, or JM216. The formation of protein-DNA complexes that contained hMSH2 and hMLH1 was documented by mobility shift assay when nuclear extracts were incubated with DNA platinated with cisplatin but not with oxaliplatin. These results demonstrate a correlation between failure of the DNA mismatch repair proteins to recognize the platinum adduct and low-level resistance, suggesting a role for the DNA mismatch repair system in generating signals that contribute to the generation of apoptotic activity. They also identify the use of drugs whose adducts are not recognized as a strategy for circumventing resistance due to loss of DNA mismatch repair.
DNA错配修复功能缺失发生在多种类型的肿瘤中。利用两对具有或缺乏该功能的细胞系，测试了DNA错配修复活性缺失对顺铂及一组类似物敏感性的影响。与表达野生型hMLH1的3号染色体互补亚系相比，hMLH1缺陷的人结肠癌细胞系HCT116+ch2对顺铂的耐药性高2.1倍，对卡铂的耐药性高1.3倍。同样，与具有野生型hMSH2的2号染色体互补亚系相比，hMSH2缺陷的人子宫内膜癌细胞系HEC59对顺铂的耐药性高1.8倍，对卡铂的耐药性高1.5倍。与在DNA中形成相同类型加合物的顺铂和卡铂不同，对于奥沙利铂、四铂、反铂、JM335或JM216，DNA错配修复功能正常和缺陷的细胞系之间的敏感性没有差异。当核提取物与顺铂铂化的DNA孵育时，通过迁移率变动分析记录了含有hMSH2和hMLH1的蛋白质-DNA复合物的形成，但与奥沙利铂孵育时未观察到。这些结果表明，DNA错配修复蛋白无法识别铂加合物与低水平耐药性之间存在相关性，提示DNA错配修复系统在产生有助于凋亡活性产生的信号中发挥作用。它们还确定了使用其加合物不被识别的药物作为规避因DNA错配修复缺失导致的耐药性的策略。
