We investigated whether the green tea polyphenol epigallocatechin-3-gallate (EGCG) will inhibit skin tumor formation resulting from the expression of an activated ras and elevated levels of the ornithine decarboxylase (ODC), a key regulatory enzyme in the biosynthesis of polyamines. Compared to normal tissue, both animal and human tumors have high levels of ODC and polyamines. In addition, many human tumors exhibit aberrant Ras signaling either due to ras mutations or genetic lesions in other genes that lead to chronic upregulation of the Ras pathway. By crossing TG.AC v-Ha-ras and K6/ODC transgenic mice, we have previously shown that an activated ras and follicular ODC overexpression cooperate to generate spontaneous skin tumors in ODC/Ras double transgenic mice between the age of 6 to 10 weeks. EGCG (0.045% [w/v]) was administered in the drinking water of 3-week old ODC/Ras transgenic mice for 8 to 9 weeks. EGCG treatment resulted in a significant decrease in both tumor number (2 vs. 5.5) and median total tumor burden (0.09 g vs. 1.01g) compared to untreated ODC/Ras mice. The reduction in tumor burden was not solely due to a reduction in the number of tumors as evidenced by the median average tumor mass of 0.045 g in the EGCG-treated mice and 0.28 g in the control group. Although epidermal ODC activity was decreased in EGCG-treated ODC/Ras transgenic mice, polyamine levels were not significantly affected. Overall expression of G1/S- and G2/M-regulatory cyclins, including cyclin E, cyclin A, and cyclin B1, was decreased in skin tumors from EGCG treated ODC/Ras mice compared to nontreated ODC/Ras mice. In order to determine a mechanism by which EGCG reduces tumor formation, we have compared the effect of EGCG in primary cultures of keratinocytes isolated from K6/ODC transgenic mouse skin that express high levels of ODC with keratinocytes isolated from normal littermates. Whereas proliferation is not affected by EGCG exposure in wild-type keratinocytes, noncytotoxic levels (10-20 μM) of EGCG significantly decrease 3H thymidine incorporation in keratinocytes overexpressing ODC. Moreover, EGCG treatment increases both caspase-3 and bax expression in ODC overexpressing keratinocytes but not in wild-type keratinocytes. These data suggest that EGCG inhibits the formation of tumors that are driven by elevated levels of ODC and a mutated ras by preferentially blocking proliferation and stimulating apoptosis in epidermal cells possessing high levels of ODC. (Supported by NIH grants CA70739 and CA97249)

[Proc Amer Assoc Cancer Res, Volume 45, 2004]