DNA TOPOISOMERASES AS TARGET OF ACTION OF ANTICANCER DRUGS

DNA拓扑异构酶II（顶部2）是几个细胞的目标， 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）。 因此，它是 抗癌药物开发的关键目标。 通过比较 VP-16发色团和椭圆藤碱，我们进行了合理的设计 全合成制得的新药物氮杂毒素。 阿扎毒素是 具有独特DNA序列选择性的非常活跃的top 2抑制剂。 有趣的是，它不是DNA嵌入剂，它产生蛋白质- 连接的DNA在细胞中断裂。 阿扎毒素衍生物正在研究中 它们的抗肿瘤活性正在NCI药物筛选中进行评估 程序. 我们也在研究蒽吡唑类药物 在纯化的顶部2上的衍生物（DU 937和DU 941）。 DNA拓扑异构酶I（top 1）也已成为抗 自从发现喜树碱及其几种抗癌药物 喜树碱衍生物是特异性的顶级毒物， 类似物显示出有希望的抗癌活性。 我们的目标之一是 确定喜树碱抑制TOP 1的分子机制。 我们最近的研究表明，使用前1个cDNA喜树碱中毒， 特别是在切割位点处的top 1，其在其5 '- 终点站 这一观察结果与我们的其他结果一致， 光活化的喜树碱诱导特异性地在鸟嘌呤处切割。 总之，这些数据支持我们以前的药物堆积模型， 诱导的拓扑异构酶抑制（Jelvis等人，Nucleic Acids Res 1991;266：20418-23; Pomperson等人，Nucleic Acids Res 1991;19：5973-80）。 喜树碱分子药理学的另一种方法是 开发和分析喜树碱抗性细胞。 我们要找一个 中国仓鼠耐药细胞前1位cDNA的点突变 （Tanizawa和Pomanzawa，Cancer Res.1992;52：1848-54），表明 突变的区域可能对酶活性和 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-16; VM-26), mitoxantrone, amsacrine, ellipticines). For this reason, it is one of the key targets in anti-cancer drug development. By comparing the structures of the VP-16 chromophore and ellipticine, we have rationally designed azatoxin, a new drug which has been made by total synthesis. Azatoxin is a very active top 2 inhibitor with a unique DNA sequence selectivity. Interestingly, it is not a DNA intercalator, and it produces protein- linked DNA breaks in cells. Azatoxin derivatives are being investigated and their antitumor activity is being evaluated at the NCI Drug Screening Program. We are also characterizing the effect of anthrapyrazoles derivatives (DU937 & DU941) on purified top 2. DNA topoisomerase I (top 1) has also become an essential target for anti cancer 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. One of our goals is to identify the molecular mechanism(s) of top 1 inhibition by camptothecins. Our recent studies using top 1 cDNA demonstrate that camptothecin poisons specifically top 1 at the cleavage sites which have a guanine at their 5'- terminus. This observation is consistent with our other results that photoactivated camptothecin induces cleavage specifically at guanines. Together, these data support our previous drug stacking model for drug- induced topoisomerase inhibition (Jaxel et al, Nucleic Acids Res 1991;266:20418-23; Pommier et al, Nucleic Acids Res 1991;19:5973-80). Another approach to the molecular pharmacology of camptothecin has been to develop and analyze camptothecin-resistant cells. We are finding a single point mutation in the top 1 cDNA from drug-resistant Chinese hamster cells (Tanizawa and Pommier, Cancer Res. 1992;52:1848-54), indicating that the mutated region might be important for both enzymatic activity and camptothecin sensitivity.