Aebi S, Fink D, Gordon R, Kim H K, Zheng H, Fink J L, Howell S B
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla, California 92093-0812, USA.
Clin Cancer Res. 1997 Oct;3(10):1763-7.
Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.
DNA错配修复功能缺失在许多类型的散发性人类癌症以及遗传性非息肉病性结直肠癌患者所患肿瘤中都很常见。利用一对因hMSH2功能缺失而错配修复功能正常或缺陷的细胞系，以及另一对因hMLH1功能缺失而错配修复功能正常或缺陷的细胞系，测试了DNA错配修复活性缺失对一组常用化疗药物敏感性的影响。已知这些细胞对6-硫鸟嘌呤和N-甲基-N'-硝基-N-亚硝基胍耐药，因此将它们纳入测试组作为对照。两组细胞的结果一致。hMSH2或hMLH1功能缺失均与对顺铂、卡铂和依托泊苷的低水平耐药相关，但对美法仑、哌福司汀、5-氟尿嘧啶、阿霉素或紫杉醇无耐药性。这些结果与以下概念一致，即DNA错配修复蛋白作为6-硫鸟嘌呤、N-甲基-N'-硝基-N-亚硝基胍、顺铂和卡铂产生的加合物的检测器，但不是美法仑和哌福司汀的检测器。它们还表明，这些蛋白质在检测依托泊苷与拓扑异构酶II结合产生的DNA损伤以及传递有助于激活细胞凋亡的信号方面发挥作用。
