PROSTATIC TOPOISOMERASES AS THERAPEUTIC DRUG TARGETS

据估计，1994年有38,000名男性死于转移性前列腺癌。 前列腺癌的新的全身治疗策略是 迫切需要的。 靶向DNA的抗肿瘤药物 拓扑异构酶可能是最普遍有效的癌症 目前可用的化疗药物。 这些药物中的许多 是联合化疗方案的关键组成部分 能够治愈几种晚期危及生命的人类癌症。 有些甚至在治疗 难治性前列腺癌 不幸的是， 迄今为止使用的药物已经降低了惊人的死亡率 在美国，前列腺癌晚期。 本研究项目提案中提出的初步证据 拓扑异构酶靶向药物可能会激活DNA损伤， 反应信号转导途径，最终在细胞 死亡，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比在包含可治愈的恶性肿瘤的细胞中更有效。 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子 拓扑异构酶靶向药物造成的伤害可能是至关重要的 体内药物治疗功效的决定因素。 了解 拓扑异构酶靶向药物敏感性的生化决定因素 人类前列腺癌细胞所展示的将被证明是无价的 发展新的治疗策略， 前列腺癌 因此，本拟议项目的目标是：（一） 在人前列腺癌中鉴定拓扑异构酶药物靶点 细胞并定量酶表达水平，（ii.）到 表征通过以下方式显示的生化耐药决定簇： 拓扑异构酶靶向的人前列腺癌耐药细胞 sublines，（iii.）研究MDR 1介导的药物的获得 人前列腺癌细胞的抗性，和（iv.）进行 前列腺癌新疗法的临床前疗效评估 拓扑异构酶靶向药物治疗人类肿瘤的策略 肿瘤异种移植物

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.