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: 3838030
• 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/3838030
• 关键词: DNA topoisomerases; active sites; animal tissue; antineoplastics; camptothecin; drug design /synthesis /production; drug metabolism; enzyme complex; enzyme inhibitors; enzyme mechanism; guanine; nucleic acid sequence; point mutation; protein structure function

DNA topoisomerase II (top 2) is the cellular target of several among the most potent anticancer agents (Doxorubicin, etoposides [VP16; VM-26], mitoxantrone, amsacrine, ellipticines). For this reason, it is one of the key targets in anticancer 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 was found to be an active top 2 inhibitor with a unique DNA sequence selectivity in the presence of purified top 2. Interestingly, it is not a DNA intercalator, and it produces protein-linked DNA breaks in cells. A patent has been filed for azatoxin and its antitumor activity is being evaluated. DNA topoisomerase I (top 1) has also 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. 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 specifically poisons 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 campothecin-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. 1991; 52: 1848-54), indicating that the mutated region might be important for both enzymatic activity and camptothecin sensitivity.

DNA 拓扑异构酶 II（顶部 2）是多种酶的细胞靶标 最有效的抗癌药物（阿霉素、依托泊苷 [VP16；VM-26]、 米托蒽醌、安吖啶、玫瑰树碱）。 由于这个原因，它是其中之一 抗癌药物开发的关键目标。 通过比较 VP-16发色团和玫瑰树碱的结构，我们有理有据 设计了全合成新药氮杂毒素。 Azatoxin 被发现是具有独特 DNA 的活性 Top 2 抑制剂 纯化的 top 2 存在下的序列选择性。有趣的是，它 不是 DNA 嵌入剂，它会产生与蛋白质相关的 DNA 断裂 细胞。 氮杂毒素及其抗肿瘤活性已申请专利 正在评估中。 DNA 拓扑异构酶 I（top 1）也已成为重要靶标 自从发现喜树碱和几种 其衍生物是特定的排名第一的毒物，并且是水溶性的 喜树碱类似物表现出有前景的抗癌活性。 我们的一员 目标是确定前 1 个抑制的分子机制 喜树碱。 我们最近使用 top 1 cDNA 进行的研究表明 喜树碱专门毒害top 1的裂解位点，该位点具有 5' 末端有一个鸟嘌呤。 这个观察结果与我们的一致 光活化喜树碱诱导裂解的其他结果 特别是鸟嘌呤。 这些数据共同支持了我们之前的药物 药物诱导的拓扑异构酶抑制的堆积模型（Jaxel 等人， 核酸研究。 1991；266：20418-23； Pommier 等人，核酸研究。 1991；19：5973-80）。 分子药理学的另一种方法 喜树碱一直致力于开发和分析喜树碱抗性细胞。 我们在前 1 个 cDNA 中发现了一个单点突变 耐药中国仓鼠细胞（Tanizawa 和 Pommier，Cancer Res. 1991； 52: 1848-54)，表明突变区域可能很重要 用于酶活性和喜树碱敏感性。