Fink D, Zheng H, Nebel S, Norris P S, Aebi S, Lin T P, Nehmé A, Christen R D, Haas M, MacLeod C L, Howell S B
Department of Medicine, University of California, San Diego, La Jolla 92093, USA.
Cancer Res. 1997 May 15;57(10):1841-5.
In vitro studies have shown that loss of DNA mismatch repair due to lack of either hMSH2 or hMLH1 activity results in low-level resistance to cisplatin but not to oxaliplatin, an analogue that produces a different type of DNA adduct. No information is currently available on whether this low-level resistance is sufficient to result in enrichment of mismatch repair-deficient cells during drug exposure in vitro or to account for clinical failure of treatment in vivo. Mixed populations of cells containing a minority of DNA mismatch repair-deficient cells constitutively expressing green fluorescence protein were exposed repeatedly in vitro to cisplatin and oxaliplatin. Treatment with cisplatin resulted in a gradual enrichment for DNA mismatch repair-deficient cells, whereas treatment with oxaliplatin did not. MSH2-/- and MSH2+/+ embryonic stem cells were established as xenografts in athymic nude mice. Animals were treated 48 h after tumor implantation with a single LD10 dose of either cisplatin or oxaliplatin. MSH2-/- tumors were significantly less responsive to cisplatin than MSH2+/+ tumors, whereas there was no difference in sensitivity to oxaliplatin. These results demonstrate that the degree of cisplatin resistance conferred by loss of DNA mismatch repair is sufficient to produce both enrichment of mismatch repair-deficient cells during treatment in vitro and a large difference in clinical responsiveness in vivo. The results identify loss of DNA mismatch repair as a mechanism of resistance to cisplatin but not oxaliplatin.
体外研究表明，由于缺乏hMSH2或hMLH1活性而导致的DNA错配修复功能丧失会导致对顺铂产生低水平耐药，但对奥沙利铂不产生耐药，奥沙利铂是一种能产生不同类型DNA加合物的类似物。目前尚无信息表明这种低水平耐药是否足以在体外药物暴露期间导致错配修复缺陷细胞富集，或解释体内治疗的临床失败。将组成性表达绿色荧光蛋白的少数DNA错配修复缺陷细胞的混合细胞群体在体外反复暴露于顺铂和奥沙利铂。用顺铂处理导致DNA错配修复缺陷细胞逐渐富集，而用奥沙利铂处理则不会。将MSH2-/-和MSH2+/+胚胎干细胞作为异种移植物植入无胸腺裸鼠体内。在肿瘤植入后48小时，用单一LD10剂量的顺铂或奥沙利铂对动物进行治疗。MSH2-/-肿瘤对顺铂的反应明显低于MSH2+/+肿瘤，而对奥沙利铂的敏感性没有差异。这些结果表明，DNA错配修复功能丧失所赋予的顺铂耐药程度足以在体外治疗期间导致错配修复缺陷细胞富集，并在体内临床反应方面产生巨大差异。这些结果确定DNA错配修复功能丧失是对顺铂而非奥沙利铂的耐药机制。
