Prostate cancer (PCA) ranks as the most common cancer of males in the United States and, next only to lung cancer, is the second leading cause of cancer-related deaths in American males. According to projections by the American Cancer Society, a total of 179,000 men will be diagnosed with prostate cancer in the United States in the year 1999, and 37,000 prostate cancer-related deaths are predicted this year. Because of limited treatment options and diagnostic approaches, presently prostate cancer accounts for ~29% of all cancers diagnosed in American males, with ~13% of the total cancer-related deaths in men. At present, there are woefully inadequate treatment options for advanced prostatic cancer, and the current preferred therapy for advanced stage prostate cancer is hormone ablation. Most men with this non-organ-confined disease undergo palliation with radiation or androgen ablation. To reduce the incidence of prostate cancer, chemoprevention through dietary intervention appears to be a practical and encouraging approach. Extensive studies from this and other laboratories over the last 10 years have verified cancer chemopreventive effects of green tea, which next only to water, is the most popular beverage in the world. Many epidemiological studies also have demonstrated the effectiveness of green tea against a variety of cancers.

In laboratory studies in cell culture systems and in animal models, as well as in epidemiological studies, green tea polyphenols have shown promise against PCA. Further, the Chinese population, which widely consumes green tea on a regular basis, has the lowest incidence of PCA from among five continents. Studies conducted in this laboratory, in cell culture system and in animals, also support the choice of green tea polyphenols as attractive agents to intervene against PCA. Our recent studies have shown that epigallocatechin-3-gallate (EGCG), the major polyphenol present in green tea, is capable of imparting inhibitory effects against the growth of PCA cells by eliminating both androgen-sensitive as well as androgen-insensitive cells by (1) modulation in cell proliferation and (2) programmed cell death, i.e., `apoptosis.¿ This is an important observation because the regulation of normal growth, development, and function of the prostate is intimately associated with androgen action. The initial response to androgen ablation generally results in tumor shrinkage due to the apoptotic death of androgen-sensitive PCA cells. However, the apoptotic pathway is not activated by androgen ablation or by cytotoxic drugs in androgen-insensitive cells. Generally, a patient¿s death relates directly to the proliferation of this subpopulation of cells. It is also important to note that at the time of clinical diagnosis, most PCAs represent a mixture of androgen-sensitive and androgen-insensitive cells. Therefore, the key to the control of PCA appears to lie in the elimination of both types of cells through mechanism-based preventive/therapeutic approaches.

The innovative idea of this proposal is to test the hypothesis that EGCG will impart cancer- preventive/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 EGCG treatment will reduce serum PSA levels that are considered a marker of prostate cancer burden.

In this proposal, we will employ the athymic nude mouse and transgenic adenocarcinoma mouse prostate (TRAMP) models to investigate (1) the prostate cancer chemopreventive potential of EGCG and (2) the modulations in cell cycle and apoptotic machinery during the antiproliferative response of EGCG. It is important to emphasize here that the TRAMP model, to our understanding, is the most suitable model available at present for PCA studies because it has been shown to display progressive forms of PCA without any chemical treatment and the PCA developed in this model histologically resembles human disease as it metastasizes to bones and lungs. The final aim of this proposal is to investigate if EGCG treatment results in a reduction in serum prostate specific antigen (PSA) level, which, for humans, is a widely accepted model for prostate cancer burden. In the nude mice transplanted with 22Rvl cells, which make PSA, we will study the effect of EGCG treatment on serum PSA levels.

A successful completion of this proposal may result in the development of novel strategies against PCA that may have implications for human situations.