Aebi S, Kurdi-Haidar B, Gordon R, Cenni B, Zheng H, Fink D, Christen R D, Boland C R, Koi M, Fishel R, Howell S B
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla 92093-0812, USA.
Cancer Res. 1996 Jul 1;56(13):3087-90.
Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutations in genes involved in DNA mismatch repair and thereby to resistance to DNA-alkylating agents. Parental cells of the human ovarian adenocarcinoma cell line 2008 expressed hMLH1 when analyzed with immunoblot. One subline selected for resistance to cisplatin (2008/A) expressed no hMLH1, whereas another (2008/C135.25) expressed parental levels. Microsatellite instability was readily demonstrated in 2008/A cells but not in 2008 and in 2008/C135.25 cells. In addition, the 2008/A cells were 2-fold resistant to methyl-nitro-nitrosoguanidine and had a 65-fold elevated mutation rate at the HPRT locus as compared to 2008 cells, both of which are consistent with the loss of DNA mismatch repair in these cells. To determine whether the loss of DNA mismatch repair itself contributes to cisplatin resistance, studies were carried out in isogenic pairs of cell lines proficient or defective in this function. HCT116, a human colon cancer cell line deficient in hMLH1 function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLH1. Similarly, the human endometrial cancer cell line HEC59, which expresses no hMSH2, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 2 that expresses hMSH2. Therefore, the selection of cells for resistance to cisplatin can result in the loss of DNA mismatch repair, and loss of DNA mismatch repair in turn contributes to resistance to cisplatin.
选择对顺铂（一种广为人知的诱变剂）具有抗性的细胞，可能会导致参与DNA错配修复的基因突变，从而产生对DNA烷化剂的抗性。用人卵巢腺癌细胞系2008的亲本细胞进行免疫印迹分析时，可检测到hMLH1的表达。一个对顺铂具有抗性的亚系（2008/A）不表达hMLH1，而另一个亚系（2008/C135.25）表达水平与亲本相同。微卫星不稳定性在2008/A细胞中很容易被检测到，但在2008细胞和2008/C135.25细胞中未检测到。此外，2008/A细胞对甲基硝基亚硝基胍具有2倍抗性，与2008细胞相比，其在HPRT位点的突变率提高了65倍，这两者均与这些细胞中DNA错配修复功能的丧失一致。为了确定DNA错配修复功能的丧失本身是否会导致顺铂抗性，对具有或缺乏该功能的同基因细胞系进行了研究。HCT116是一种缺乏hMLH1功能的人结肠癌细胞系，与补充了3号染色体并表达hMLH1的亚系相比，它对顺铂具有2倍抗性。同样，不表达hMSH2的人子宫内膜癌细胞系HEC59，与补充了2号染色体并表达hMSH2的亚系相比，对顺铂也具有2倍抗性。因此，选择对顺铂具有抗性的细胞会导致DNA错配修复功能的丧失，而DNA错配修复功能的丧失反过来又会导致对顺铂的抗性。
