Prostate cancer, diagnosed in an estimated 200,000 men in 1994, presents a formidable public health challenge. Unfortunately, treatments for advanced prostate cancers are woefully inadequate: some 38,000 men likely died of prostate cancer in 1994. Clearly, new strategies for prostate cancer prevention are desperately needed. The focus of this proposed project is to undertake an evaluation of a new prostate cancer prevention strategy involving therapeutic biomodulation of carcinogen detoxification enzymes in prostatic epithelial cells. Exciting preliminary data suggest that prostate cancers may arise from prostatic epithelial cells with defects in electrophilic carcinogen detoxification capabilities. Specifically, the GSTP1 gene, encoding the human pi class glutathione S-transferase (GST), appears to be nearly uniformly inactivated during the process of prostatic carcinogenesis. These new findings provide a plausible mechanistic link between the molecular pathogenesis of human prostate cancer and known epidemiological data implicating environmental factors as major contributors to the prostate cancer epidemic in the United States, Perhaps, prostatic epithelial cells with compromised defenses against environmental electrophilic carcinogens may be exquisitely vulnerable to neoplastic transformation and malignant progression. If this hypothesis were true, a rational prostate cancer prevention strategy might focus on augmenting electrophile detoxification capacity in prostatic cells to attenuate or abrogate prostatic carcinogenesis. This proposed study aims to pursue a preclinical evaluation of therapeutic electrophile detoxification enzyme induction, with special attention to induction of GSTs, as a translational research project. The potential efficacy of GST inducers (such as the drug oltipraz) as prostate cancer prevention agents will be assessed using the Lobund-Wistar rat model of prostatic carcinogenesis. Additional candidate GST inducers potentially useful for human prostate cancer prevention will be identified using a new rapid in vitro screening assay to survey a number of chemical compounds and dietary (vegetable) preparations. Finally, methods for monitoring GST biomodulation in prostatic tissues will be developed to facilitate future clinical assessment of GST induction strategies for prostate cancer prevention. Hopefully, the productive pursuit of the proposed study aims will permit rational clinical evaluation of GST inducers as prostate cancer prevention agents in clinical trials and will facilitate progress toward preventing the devastating morbidity and mortality associated with prostate cancer.
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