This is a competitive renewal application of our grant through which we have made significant progress and published several papers demonstrating cancer chemopreventive effects of green tea. We have also made significant contribution in establishing the mechanisms of chemopreventive effects of green tea and its polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG) in cell culture and in animal model systems. Our novel findings published in Proc. Natl. Acad. Sci. USA (98:10350-5, 2001) showed that oral infusion of green tea polyphenols (GTP) at a human achievable dose (equivalent to six cups of green tea per day), in a transgenic adenocarcinoma of the mouse prostate (TRAMP), a model that mimics progressive forms of human prostatic disease, results in significant inhibition of prostate carcinogenesis possibly through induction of apoptosis of prostate cancer cells. This continuation proposal lays out a plan to investigate stages of PCA development where green tea is most effective as a chemopreventive or chemotherapeutic agent. The TRAMP model provides a unique window of opportunity for studies on agents that can interfere at well-defined stages of PCA development. We hypothesize that oral infusion of GTP at well-defined stages of PCA progression will prevent the conversion of normal prostate to prostatic intraepithelial neoplasia (PIN) to histologic cancer and finally to metastatic carcinoma in TRAMP mice. We will assess the effect of GTP on different stages of PCA development in TRAMP mice. During the course of our study in vivo tumor growth will be monitored serially during the experimental protocol by magnetic resonance imaging and in vivo apoptosis will be monitored throughout the protocol by our recently developed novel technique using 99mTc-labeled annexin V imaging. Cancer chemotherapeutic effects of GTP on PCA will be verified using a nude mouse model system implanted with androgen-responsive 22Rvl and androgen-unresponsive PC3 cells. Based on our in vitro findings we hypothesize that the chemopreventive and chemotherapeutic effects of GTP are mediated through its ability to block the cell cycle progression followed by an induction of apoptosis. We will test this hypothesis via evaluating the effect of GTP on the modulations in cyclin kinase inhibitor-cyclin-cyclin dependent kinase network. We are proposing to use GTP instead of a pure agent because it directly reflects human situation. In order to avoid complications associated with caffeine present in green tea, we will employ decaffeinated GTP. The hypothesis to be tested in this proposal is that decaffeinated green tea will impart cancer-preventive and possibly cancer-therapeutic effects by modulating cell cycle- and apoptotic- machinery of PCA cells irrespective of their androgen association. A corollary to this hypothesis that will be tested in this proposal is that oral consumption of green tea will reduce levels of serum PSA and IGF-I and restore IGFBP3 levels. This proposal may be extremely valuable pre-clinical approach against PCA in humans.
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