甲基化抗肿瘤药物治疗中的DNA修复:治疗效果与健康结局

doi:10.3969/j.issn.1004-616x.2016.05.001

Abstract

Abstract: For patients who are treated with anti-cancer drugs,DNA repair is often a critical mechanism,which determines therapeutic efficacy and/or adverse biological consequences such as mutagenesis,carcinogenesis and teratogenesis. This brief review is focused onto DNA repair activities on damage resulting from exposure to methylating anticancer drugs. Although these drugs unselectively target DNA from cancer and normal cells,the cancer-specific killing effect is likely due to downregulation of specific DNA repair activities,thereby killing more cancer than normal cells. The monofunctional alkylating agents exhibit methylating properties (procarbazine,dacarbazine,streptozotocine, temozolomide) or they chloroethylate the DNA forming monoadducts and,in a second step,DNA interstrand crosslinks (lomustine,nimustine,carmustine,fotemustine). A major mechanism of defense of cancer cells to these drugs is direct reversal of the critical DNA damage,O⁶-methylguanine as well as O⁶-chloroethylguanine,by the suicide enzyme O⁶-methylguanine-DNA methyltransferase (MGMT),which represents an important drug resistance marker especially in high-grade malignant gliomas. Since MGMT has a significant impact on the outcome of anti-cancer therapy,it is a predictive marker of the effectiveness of methylating anticancer drugs,and clinical trials are underway analyzing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair,DNA double-strand break (DSB) repair by homologous recombination and DSB signaling. Base excision repair and alkB homologous proteins (such as ABH2) might also contribute to alkylating drug resistance notably in cells expressing a high amount of MGMT. Better understanding of these mechanisms will be helpful in designing more effective therapies that have less adverse outcomes.

Key words: temozolomide, O⁶-methylguanine-DNA methyltransferase, alkyltransferase, promoter methylation, DNA repair, cancer, biomarker, drug resistance, glioblastoma

CLC Number:

R730.5

Bernd Kaina. DNA repair in cancer therapy with methylating anticancer drugs: improving therapeutic efficacy and reducing side effects[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2016, 28(5): 333-341,347.

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DNA repair in cancer therapy with methylating anticancer drugs: improving therapeutic efficacy and reducing side effects

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