Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols

Development of effective chemopreventive agents against prostate cancer (Ca P) for humans requires conclusive evidence of their efficacy in animal mode ls that closely emulates human disease. The autochthonous transgenic adenoc arcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human di sease. Employing male TRAMP mice, we show that oral infusion of a polypheno lic fraction isolated from green tea (GTP) at a human achievable dose (equi valent to six cups of green tea per day) significantly inhibits CaP develop ment and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20),65% (13 of 20),40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metasta ses to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (i) significant delay in primary tumor inc idence and tumor burden as assessed sequentially by MRI, (ii) significant d ecrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) signif icant inhibition in serum insulin-like growth factor-I and restoration of i nsulin-like growth factor binding protein-3 levels, and (iv) marked reducti on in the protein expression of proliferating cell nuclear antigen (PCNA) i n the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significan t apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.