Calderón-Montaño José Manuel, Burgos-Morón Estefanía, Orta Manuel Luis, López-Lázaro Miguel
Department of Pharmacology, Faculty of Pharmacy, University of Seville, C/ Profesor Garcia Gonzalez, 41012, Sevilla, Spain.
Curr Med Chem. 2014;21(30):3419-54. doi: 10.2174/0929867321666140601203816.
Tumor cells often have defects in DNA repair pathways that make them vulnerable to specific DNA-damaging anticancer agents. The identification of DNA repair defects in tumor cells and the evaluation of their influence on the cytotoxicity of anticancer drugs are active areas of scientific investigation that may help rationalize and improve cancer chemotherapy. This article reviews the available data on the influence of defects in proteins involved in the major DNA repair pathways (i.e., homologous recombination, non-homologous end joining, base excision repair, nucleotide excision repair, mismatch repair, Fanconi anemia repair, translesion synthesis and direct reversal repair) on the cytotoxicity of the FDA-approved anticancer drugs. It is shown that specific deficiencies in these DNA repair pathways alter the cytotoxicity of 60 anticancer drugs, including classical DNA-targeting drugs (e.g., alkylating agents, cytotoxic antibiotics, DNA topoisomerase inhibitors and antimetabolites) and other drugs whose primary pharmacological target is not the DNA (e.g., antimitotic agents, hormonal and targeted therapies). This information may help predict response to anticancer drugs in patients with tumors having specific DNA repair defects.
肿瘤细胞在DNA修复途径中常常存在缺陷，这使得它们对特定的DNA损伤性抗癌药物敏感。识别肿瘤细胞中的DNA修复缺陷以及评估其对抗癌药物细胞毒性的影响，是科学研究的活跃领域，可能有助于使癌症化疗更加合理并得到改进。本文综述了有关主要DNA修复途径（即同源重组、非同源末端连接、碱基切除修复、核苷酸切除修复、错配修复、范可尼贫血修复、跨损伤合成和直接逆转修复）中相关蛋白缺陷对FDA批准的抗癌药物细胞毒性影响的现有数据。结果表明，这些DNA修复途径中的特定缺陷会改变60种抗癌药物的细胞毒性，包括经典的DNA靶向药物（如烷化剂、细胞毒性抗生素、DNA拓扑异构酶抑制剂和抗代谢物）以及其他主要药理学靶点不是DNA的药物（如抗有丝分裂剂、激素疗法和靶向疗法）。这些信息可能有助于预测患有特定DNA修复缺陷肿瘤的患者对抗癌药物的反应。
