Involvement of the DNA mismatch repair system in antineoplastic drug resistance

被引:106
作者
Lage, H [1 ]
Dietel, M [1 ]
机构
[1] Humboldt Univ, Inst Pathol, D-10117 Berlin, Germany
关键词
DNA-mismatch repair; drug resistance; MLH1; MSH2; MSH3; MSH6; PMS2; MutS; MutL;
D O I
10.1007/s004320050258
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Different types of antineoplastic drugs, such as the alkylating agents busulfan, N-methyl-N'-nitro-nitrosoguanidine, N-methyl-N-nitrosourea, procarbazine and temozolomide, the antimetabolites, mercaptopurine and 6-thioguanine, the platinum compounds carboplatin and cisplatin, the anthracycline doxorubicin and the epipodophyllotoxine etoposide act by damaging DNA directly or indirectly. Increasing evidence has shown that tumours could acquire resistance to these drugs by loss of DNA-mismatch repair (MMR) activity. This phenomenon is caused by a decreased MMR-dependent stimulation of signal-transduction pathways causing programmed cell death. Simultaneously, the mutation rate in MMR-deficient tumours is increasing, which could lead to additional secondary drug/resistance phenotypes to other antineoplastic agents. In addition to this, an enhanced mutation rate may contribute to increased phenotypic variation and therefore the clinical aggressiveness of primary tumours and their metastases.
引用
收藏
页码:156 / 165
页数:10
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