DNA TOPOISOMERASES AS TARGET OF ACTION OF ANTICANCER DRUGS

DNA拓扑异构酶II（顶部2）是几种DNA拓扑异构酶的细胞靶标。 在最有效的抗癌剂（多柔比星、依托泊苷 [VP-16; VM-26]、米托蒽醌、安吖啶、椭圆形碱）。 为此 因此，它是抗癌药物的关键靶点之一， 发展 我们进一步鉴定了氮杂毒素衍生物 这两个顶部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， 蒽吡唑衍生物（DU 937和DU 94 l），其在临床上 试验是两大抑制剂。 DNA拓扑异构酶1（top 1）已成为一个重要的目标， 抗癌研究，因为发现喜树碱和 它的几种衍生物是特定的顶级毒药， 水溶性喜树碱类似物显示出有希望的抗癌活性 活动 Saintopin是一种双重top 1和top 2抑制剂。我们有 对圣托品切割位点进行测序， 对于top 1和top 2，鸟嘌呤是强烈优选的， 断裂的5 ′-末端。 这一结果与我们的 假设药物结合在DNA和DNA的界面上， 酵素 药物拓扑异构酶分子的另一种途径 研究和分析抗喜树碱的 细胞 我们已经表征了前1个cDNA中的突变， 两种喜树碱耐药细胞系的氨基酸点突变 这表明选择性酶区域对这两种酶都很重要， 酶活性和喜树碱敏感性。

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.