PROTEIN-ASSOCIATED DNA BREAKS AS INDICATOR OF TOPOISOMERASE INHIBITION

蛋白质相关 DNA 断裂作为拓扑异构酶抑制的指标

• 批准号: 3916548
• 负责人: Y POMMIER
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3916548
• 关键词: DNA binding protein; DNA repair; DNA topoisomerases; acridines; antineoplastics; breast neoplasms; camptothecin; doxorubicin; drug adverse effect; drug metabolism; drug resistance; enzyme inhibitors; enzyme mechanism; etoposide; genetic transcription; molecular oncology; neoplasm /cancer chemotherapy; neoplastic cell; neoplastic cell culture for noncancer research; podophyllin; radiation carcinogenesis

DNA topoisomerases have been identified as major targets for cancer chemotherapy. Two types of topoisomerases have been isolated from eukaryotic cell nuclei. Both topoisomerases 1 & II relax DNA supercoiling and play a crucial role in DNA replication and transcription. However, topoisomerase II is the only enzyme able to anchor DNA loops to the nuclear matrix and to decatenate newly replicated DNA circles. Two families of anticancer drugs inhibit topoisomerase II: DNA intercalators, such as amsacrine (m-AMSA), adriamycin and ellipticine derivatives, and demethylepipodophyllotoxins, such as etoposide (VP-16) and teniposide (VM-26). Drug-induced topoisomerase II inhibition results in the formation of protein-associated DNA breaks, which can be detected by alkaline elution. We have shown now, that the specific topoisomerase I inhibitor, camptothecin produces also protein-associated DNA breaks. Our recent finding that the DNA breaks induced by topoisomerase inhibitors are associated with strong and poorly reversible DNA synthesis inhibition, and that aphidicolin prevents the cytotoxicity of topoisomerase inhibitors suggest that drug-induced topoisomerase complexes could exert their cytotoxic action by producing stable topoisomerase-DNA complexes which would destabilize DNA replication complexes. Finally, we have found that a human breast cancer cell line (MCF-7) resistant to adriamycin has topoisomerase 11 modifications, which are associated with the drug uptake reduction usually encountered in pleiotropic resistant cell lines.

DNA拓扑异构酶已被确定为癌症的主要靶标 化疗 两种类型的拓扑异构酶已被分离， 真核细胞核 拓扑异构酶1和II都使DNA松弛 在DNA复制中起着至关重要的作用， 转录。 然而，拓扑异构酶II是唯一能够 将DNA环锚在核基质上， 复制DNA圈 两个家族的抗癌药物抑制 拓扑异构酶II：DNA嵌入剂，如安吖啶（m-AMSA）， 阿霉素和椭圆藤碱衍生物，和 去甲基表鬼臼毒素，如依托泊苷（VP-16）和 替尼泊苷（VM-26）。 药物诱导的拓扑异构酶II抑制 导致蛋白质相关DNA断裂的形成， 可通过碱性洗脱来检测。 我们现在已经证明， 特异性拓扑异构酶I抑制剂，喜树碱还产生 蛋白质相关的DNA断裂。 我们最近发现 拓扑异构酶抑制剂诱导的断裂与 强和弱可逆的DNA合成抑制， aphidicolin防止拓扑异构酶抑制剂的细胞毒性 表明药物诱导的拓扑异构酶复合物可以发挥其 通过产生稳定的拓扑异构酶-DNA复合物的细胞毒作用 这会破坏DNA复制复合体的稳定性 最后我们 已经发现一种人类乳腺癌细胞系（MCF-7）耐药， 具有拓扑异构酶11修饰， 与药物摄取减少通常遇到的， 多效性抗性细胞系。