TOPOISOMERASE II AS TARGET OF ACTION OF ANTICANCER DRUG

拓扑异构酶 II 作为抗癌药物的作用靶点

• 批准号: 3939497
• 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/3939497
• 关键词: DNA gyrase; antineoplastic antibiotics; antineoplastics; cell nucleus; crosslink; doxorubicin; drug adverse effect; drug metabolism; genetic mapping; neoplasm /cancer pharmacology; nucleic acids; podophyllin; radiotracer; simian virus 40; spermidine; spermine

DNA topoisomerases II (topo II) cause the DNA breaks and DNA- protein crosslinks observed upon exposure of mammalian cells to antitumor DNA intercalators (adriamycin, amsacrine, ellipticine) and demethylepipodophyllotoxins (VP-16, VM-26). Topo II can be purified from mouse leukemia L1210 and Chinese hamster lung fibroblasts (DC3F and DC3F/9-OHE) by FPLC. We have shown previously that drug-induced DNA breaks and DNA-protein crosslinks can be reproduce in purified systems. A method has been developed which allows the mapping of drug-induced topo II- mediated DNA break sites by using (32P)-end labeled DNAs, agarose or sequencing gels, autoradiography and computer analysis. Drug-induced DNA cleavage sites were mapped within SV40 DNA. Drugs appeared to enhance DNA cleavage at sites that were already cut by topo II alone. Each chemical class of topo II inhibitors exhibited a selective enhancement pattern. In the case of amsacrine derivatives, DNA intercalation was not correlated with topo II inhibition potency and DNA sequence selectively of binding did not influence the cleavage pattern. Thus the differential enhancement of DNA cleavage sites by topo II inhibitors may explain differential drug cytotoxicity. A second type of studies was to investigate the effects of DNA groove binders upon topo II. Polyamines (spermine, spermidine) were shown to modulate topo II DNA catalytic activities and drug- induced topo II breaks. DNA binding of the minor groove binder, distamycin was shown to change the distribution of drug-induced topo II-mediated DNA breaks. Finally, drug effects upon purified topo I were also studied. DNA intercalators appear to inhibitors topo I and this effect may contribute to the antitumor activity of these drugs.

DNA拓扑异构酶II （topo II）引起DNA断裂和DNA-