DNA TOPOISOMERASES AS TARGET OF ACTION OF ANTICANCER DRUGS

DNA拓扑异构酶作为抗癌药物的作用靶点

• 批准号: 3752316
• 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/3752316
• 关键词: DNA topoisomerases; active sites; analog; anthracyclines; antineoplastics; benzanthracenes; camptothecin; complementary DNA; drug design /synthesis /production; drug hypersensitivity; drug interactions; enzyme activity; enzyme inhibitors; etoposide; nucleic acid sequence; point mutation; tissue /cell culture; tubulin

DNA topoisomerase II (top 2) is the cellular target of several among the most potent anticancer agents (Doxorubicin, etoposides [VP-l6; VM-26], mitoxantrone, amsacrine, ellipticines). For this reason, it is one of the key targets in anticancer drug development. We have further characterized azatoxin derivatives that are both top 2 and tubulin inhibitors and have obtained pure top 2 and pure tubulin inhibitors. We have also shown that the anthrapyrazoles derivatives (DU937 and DU94l) that are in clinical trials are top 2 inhibitors. DNA topoisomerases 1 (top 1) has become an essential target for anticancer research since the discovery that camptothecin and several of its derivatives are specific top 1 poisons and that water-soluble camptothecin analogs exhibit promising anticancer activity. Saintopin is a dual top 1 and top 2 inhibitor. We have sequenced the saintopin cleavage sites and found for the first time that for both top 1 and top 2, a guanine is strongly preferred at the 5'-termini of the breaks. This result is consistent with our hypothesis that the drug bind at the interface of the DNA and the enzyme. Another approach to the drug-topoisomerase molecular interactions has been to develop and analyze camptothecin-resistant cells. We have characterized mutations in top 1 cDNA leading to amino acid point mutations in two camptothecin-resistant cell lines indicating that selective enzyme regions are important for both enzymatic activity and camptothecin sensitivity.

DNA 拓扑异构酶 II（顶部 2）是多种药物的细胞靶标 最有效的抗癌药物之一（阿霉素、依托泊苷 [VP-l6； VM-26]、米托蒽醌、安吖啶、玫瑰树碱）。 为了这 因此，它是抗癌药物的关键靶点之一 发展。 我们进一步表征了氮杂毒素衍生物 都是 Top 2 和微管蛋白抑制剂，并已获得纯 Top 2 和纯微管蛋白抑制剂。 我们还表明， 临床中的蒽吡唑衍生物（DU937 和 DU94l） 试验是前 2 个抑制剂。 DNA 拓扑异构酶 1（top 1）已成为重要靶标 自从发现喜树碱和 它的几种衍生物是特定的顶级毒物，并且 水溶性喜树碱类似物表现出有前景的抗癌作用 活动。 Saintopin 是一种双重 Top 1 和 Top 2 抑制剂。我们有 对 Saintopin 切割位点进行测序并首次发现 对于 top 1 和 top 2 来说，鸟嘌呤是强烈优选的 断裂的 5' 末端。 这个结果和我们的一致 假设药物结合在 DNA 和 DNA 的界面上 酶。 药物拓扑异构酶分子的另一种途径 相互作用已开发和分析喜树碱抗性 细胞。 我们已经确定了前 1 个 cDNA 中的突变，导致 两种喜树碱抗性细胞系的氨基酸点突变 表明选择性酶区域对于两者都很重要 酶活性和喜树碱敏感性。