PROSTATIC TOPOISOMERASES AS THERAPEUTIC DRUG TARGETS

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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.