PROSTATIC TOPOISOMERASES AS THERAPEUTIC DRUG TARGETS

前列腺拓扑异构酶作为治疗药物靶点

• 批准号: 6237375
• 负责人: WILLIAM George NELSON
• 金额: $ 16.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237375
• 关键词: DNA topoisomerases; antineoplastics; athymic mouse; clinical research; drug resistance; enzyme inhibitors; gene expression; human tissue; prostate neoplasms; tissue /cell culture; DNA topoisomerases; antineoplastics; athymic mouse; clinical research; drug resistance; enzyme inhibitors; gene expression; human tissue; prostate neoplasms; tissue /cell culture

An estimated 38,000 men died of metastatic prostate cancer in 1994. New systemic treatment strategies for prostate cancer are desperately needed. Antineoplastic drugs targeted at DNA topoisomerases may be among the most generally effective cancer chemotherapeutic drugs currently available. Many of these drugs are critical components of combination chemotherapy regimens capable of curing several advanced life-threatening human cancers. Some have even displayed marginal efficacy in the treatment of hormone-refractory prostate cancer. Unfortunately, none of the agents used thus far have diminished the staggering death rate attributable to advanced prostate cancer in the United States. Preliminary evidence presented in this research project proposal suggests that topoisomerase-targeted drugs may activate DNA damage response signal transduction pathways which culminate in cell death, such as the P53-dependent apoptosis pathway, more efficiently in cells comprising curable malignancies than in prostatic carcinoma cells. Further preliminary evidence reveals that biochemical drug resistance factors limiting the cell injury inflicted by topoisomerase-targeted drugs may be critical determinants of drug treatment efficacy in vivo. Understanding the biochemical determinants of topoisomerase-targeted drug sensitivity exhibited by human prostatic carcinoma cells will prove invaluable to the development of new treatment strategies for advanced prostate cancer. Thus, the aims of this proposed project are: (i.) to identify topoisomerase drug targets in human prostate cancer cells and quantitate enzyme expression levels, (ii.) to characterize biochemical drug resistance determinants displayed by topoisomerase-targeted drug-resistant human prostate carcinoma cell sublines, (iii.) to study the acquisition of MDR1-mediated drug resistance by human prostatic carcinoma cells, and (iv.) to conduct preclinical efficacy assessments of new prostate cancer treatment strategies by using topoisomerase-targeted drugs to treat human tumor xenografts.

1994年，估计有38,000名男性死于前列腺癌。 前列腺癌的新系统治疗策略是 迫切需要。 针对DNA的抗塑性药物 拓扑异构酶可能是最有效的癌症之一 目前可用的化学治疗药物。 其中许多药物 是组合化疗方案的关键成分 能够治愈几种威胁生命的人类癌症。 有些甚至在治疗方面显示出边际功效 激素不良前列腺癌。 不幸的是，没有 到目前为止使用的代理已经降低了惊人的死亡率 归因于美国晚期前列腺癌。 该研究项目提案中提供的初步证据 表明以拓扑异构酶为靶向的药物可能会激活DNA损伤 响应信号转导途径，在细胞中达到顶点 死亡，例如p53依赖性凋亡途径，更多 在包含可治愈的恶性肿瘤的细胞中有效 前列腺癌细胞。进一步的初步证据揭示了 限制细胞损伤的生化耐药性因子 用拓扑异构酶靶向药物造成的药物可能很关键 体内药物治疗功效的决定因素。 了解 拓扑酶靶向药物敏感性的生化决定因素 人类前列腺癌细胞展示的将证明是无价的 制定高级治疗策略 前列腺癌。 因此，该拟议项目的目的是：（i。） 鉴定人前列腺癌中的拓扑异构酶药物靶标 细胞并定量酶表达水平，（ii。） 表征由生化耐药性决定因素 拓扑异构酶靶向药物耐药的人前列腺癌细胞 Sublines，（iii。）研究MDR1介导的药物的获取 人类前列腺癌细胞的耐药性，（iv。）进行 新前列腺癌治疗的临床前疗效评估 通过使用拓扑酶靶向药物来治疗人的策略 肿瘤异种移植物。