PROSTATIC TOPOISOMERASES AS THERAPEUTIC DRUG TARGETS

据估计，1994年有38000名男性死于转移性前列腺癌。 前列腺癌的新系统治疗策略是 迫切需要。针对DNA的抗肿瘤药物 拓扑异构酶可能是最有效的癌症之一。 目前可以买到的化疗药物。这些药物中的许多 是联合化疗方案的关键组成部分 能够治愈几种威胁生命的晚期人类癌症。 有些甚至在治疗慢性阻塞性肺疾病方面显示出微效。 激素不敏感的前列腺癌。不幸的是，没有一个 到目前为止使用的药物已经降低了惊人的死亡率 可归因于美国晚期前列腺癌。 本研究项目建议书中提出的初步证据 提示以拓扑异构酶为靶点的药物可能激活DNA损伤 在细胞中达到顶峰的反应信号转导通路 死亡，如P53依赖的细胞凋亡途径，更多 在含有可治愈的恶性肿瘤的细胞中比在 前列腺癌细胞。进一步的初步证据显示 限制细胞损伤的生化耐药因素 由拓扑异构酶靶向药物引起的可能是关键 体内药物治疗效果的决定因素。了解 拓扑异构酶靶向药物敏感性的生化决定因素 人类前列腺癌细胞的展示将被证明是无价的 以开发新的晚期癌症治疗策略 前列腺癌。因此，这一拟议项目的目标是：(一) 人前列腺癌拓扑异构酶药物靶点的确定 细胞和定量酶表达水平，(ii.)至 显示的生化耐药决定因素的特征 拓扑异构酶靶向耐药人前列腺癌细胞 子行、(iii.)多药耐药相关药物的获得研究 人前列腺癌细胞的耐药性，以及(iv.)进行，进行 前列腺癌新疗法的临床前疗效评估 利用拓扑异构酶靶向药物治疗人类的策略 肿瘤异种移植。

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.