Fink D, Aebi S, Howell S B
Department of Medicine, University of California at San Diego, La Jolla 92093-0058, USA.
Clin Cancer Res. 1998 Jan;4(1):1-6.
Loss of DNA mismatch repair (MMR) has been observed in a variety of human cancers. In addition to predisposing to oncogenesis, loss of MMR activity is of concern with respect to the use of chemotherapeutic agents to treat established tumors. Loss of MMR results in drug resistance directly by impairing the ability of the cell to detect DNA damage and activate apoptosis and indirectly by increasing the mutation rate throughout the genome. The MMR proteins are involved in mediating the activation of cell cycle checkpoints and apoptosis in response to DNA damage. MMR-deficient cells have been reported to be resistant to the methylating agents procarbazine and temozolomide, the alkylating agent busulfan, the platinum-containing drugs cisplatin and carboplatin, the antimetabolite 6-thioguanine, and the topoisomerase II inhibitors etoposide and doxorubicin. In the case of cisplatin, busulfan, temozolomide, and procarbazine, the degree of resistance has been shown to be sufficient to produce a large difference in clinical responsiveness in vivo in tumor model systems. The available preclinical data suggest that tumors that contain a significant fraction of cells deficient in MMR will demonstrate reduced responsiveness to specific drugs. The challenge now is to assess the clinical significance of the presence of deficient cells in tumors and to discover drugs that retain activity against MMR-deficient cells.
在多种人类癌症中都观察到了DNA错配修复（MMR）功能的丧失。除了易引发肿瘤发生外，MMR活性的丧失在使用化疗药物治疗已形成的肿瘤方面也备受关注。MMR功能丧失直接通过损害细胞检测DNA损伤并激活凋亡的能力导致耐药性，还通过提高整个基因组的突变率间接导致耐药性。MMR蛋白参与介导细胞周期检查点的激活以及对DNA损伤的凋亡反应。据报道，MMR缺陷细胞对甲基化剂丙卡巴肼和替莫唑胺、烷化剂白消安、含铂药物顺铂和卡铂、抗代谢物6-硫鸟嘌呤以及拓扑异构酶II抑制剂依托泊苷和阿霉素具有耐药性。就顺铂、白消安、替莫唑胺和丙卡巴肼而言，耐药程度已显示足以在肿瘤模型系统中体内临床反应性方面产生很大差异。现有的临床前数据表明，含有相当一部分MMR缺陷细胞的肿瘤对特定药物的反应性会降低。目前的挑战是评估肿瘤中缺陷细胞存在的临床意义，并发现对MMR缺陷细胞仍具有活性的药物。
