Eugenol & 2-methoxyestradiol: combination approach to prostate cancer prevention

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DESCRIPTION (provided by applicant): Prostate cancer (PCA) is the second leading cause of cancer related deaths in aging males. The long-latency involved in the development of clinically significant prostate cancer, provides opportunities for successfully prevention or delay of this fatal disease using chemo or dietary compounds and is a promising approach to reduce morbidity and mortality. Preliminary studies conducted in our laboratory led to the discovery that a combination of eugenol (a spice found in cloves) and low dose of 2-methoxyestradiol (2-ME2) significantly enhanced proliferation inhibition and induced apoptosis in prostate cancer cells (US Patent #6518261B2). No studies to assess the efficacy of the combination have been reported in the literature. The goal of this pilot application submitted in response to PAR-08-055 is to determine whether the in vitro observations can be recapitulated in vivo before elaborate and detailed mechanism of action is taken up. Accordingly in this pilot application we hypothesize that "combination of 2-ME2 plus eugenol will be more effective than either single agent in preventing the development of well differentiated cancer by modulating apoptosis". This hypothesis will be tested in a mouse model of prostate cancer with high relevance to human disease. Suppression of tumor development will be monitored by (i) non-invasive Fluorine-18 fluorodeoxyglucose (FDG)-PET during progression and (ii) histological evaluation of the prostate at the termination of the experiment. Expression of apoptotic signaling molecules will be analyzed in the tissue samples using immunohistochemistry. The proposed studies will provide "proof of principle data" regarding the usefulness of the combined agents compared with each single agent in vivo. These data are essential for developing this combination for prostate cancer prevention in humans. In addition these studies will generate sufficient preliminary data that will facilitate submitting more detailed and expanded research project (R01) to (i) define the stage where the combination would be most effective; (ii) investigate the mechanism of action of this combination; and (iii) validate the identified target(s) to prevent, reverse or inhibit progression of precancerous lesions using genetic and molecular approaches.