In recent years, green tea has gained considerable interest as an agent that could reduce the risk of several cancer types. Data on cancer chemopreventive effects of green tea in many animal tumor model systems is convincing. The cancer chemopreventive effects of green tea appear to be mediated by its polyphenolic constituents (-) epigallocatechin-3-gallate (EGCG). Based on geographical observations and epidemiological evidence where Japanese and Chinese populations consuming green tea on a regular basis have the lowest incidence of PCa in the world, we hypothesized that green tea or its constituents are effective for chemopreventition of PCa. To test this hypothesis we initiated a program on chemoprevention of PCa by green tea. In our recent studies (Proc. Natl. Acad. Sci. USA 98:10350-5, 2001), employing a transgenic adenocarcinoma of the mouse prostate (TRAMP), a model that mimics progressive form of human prostatic disease, we have shown that oral infusion of a polyphenolic fraction isolated from green tea, at a human achievable dose (equivalent to six cups of green tea per day), significantly inhibits PCa development and its metastasis. One significant observation from this study was that oral infusion of green tea polyphenols resulted in an increased cancer free and overall survival of TRAMP mice. We extended these studies and more recently found that oral feeding of green tea polyphenols as the sole source of drinking fluid to TRAMP mice results in significant inhibition of vascular endothelial growth factor and matrix metalloproteases (MMP-2 and MMP-9) in dorsolateral prostate. This is an important observation suggesting the involvement of inhibition of angiogenesis and matrix degradation during green tea-mediated PCa chemoprevention. Of relevance to PCa, is the fact that once activated via certain stimuli, MMPs degrade insulin-like growth factor (IGFBP) resulting in the release of insulin-like growth factor (IGF). The present proposal capitalizes on our recent novel findings. The central hypothesis to be tested in this proposal is that """"""""EGCG imparts chemopreventive and possibly cancer therapeutic effects against PCa and its metastasis via MMP inhibition-mediated modulation in IGF/IGFBP-3 autocrine/paracrine loop"""""""". Under the proposed specific aims we will investigate i) the chemopreventive potential of EGCG against the markers of angiogenesis and metastasis in human prostate carcinoma cells, ii) the chemopreventive potential of EGCG against PCa metastasis and angiogenesis under in vivo situation in athymic nude mice implanted with PCa cells, and in TRAMP mice and iii) the chemotherapeutic potential of EGCG against PCa metastasis and angiogenesis under in vivo situation in athymic nude mice implanted with PCa cells, and in TRAMP mice. Successful completion of this project will define the molecular targets for PCa Chemoprevention by EGCG a major objective of this RFA.
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