In an earlier cancer chemoprevention study, we exposed SKH-1 mice to ultraviolet light (UV) twice a week for 22 weeks, and UV administration was stopped. The mice were tumor-free but they had hyperplasia and a high risk developing skin tumors during the next several months in the absence of further UV administration (""""""""high risk mice""""""""). This is a useful model that may be comparable to humans previously exposed to moderate/high levels of sunlight who have a high risk of developing skin cancer later in life even in the absence of continued heavy sunlight exposure. We plan to: 1. Compare the effects of orally administered green tea, decaffeinated green tea, caffeine and (-)-epigallocatechin gallate (EGCG) on the formation and growth of nonmalignant and malignant skin tumors in """"""""high risk mice."""""""" Nontumorous areas of the skin and epidermal tumors from these mice will be used for mechanism studies described in """"""""2"""""""" and """"""""3"""""""" below. 2. Determine molecular mechanisms for the effects of orally administered green tea, decaffeinated green tea, caffeine, and EGCG on the formation and growth of nonmalignant and malignant skin tumors in """"""""high risk mice. """""""" We will determine the effects of these treatments on proliferation and apoptosis and on key molecular signal transduction markers of proliferation and apoptosis in normal epidermis, hyperplastic epidermis, nonmalignant tumors and malignant tumors. 3. Determine the effects of oral administration of green tea, decaffeinated green tea, caffeine and EGCG in """"""""high risk mice? on fat levels and evaluate the relationship between decreased fat levels and inhibition of carcinogenesis. Possible relationships between lipid levels, number of tumors per mouse and tumor size per mouse in individual mice will be determined. 4. Determine the effects of short-term and long-term topical applications of EGCG, caffeine and combinations of EGCG and caffeine to """"""""high risk mice"""""""" on biomarkers of proliferation and apoptosis and on subcutaneous fat levels. Effects on the formation and growth of nonmalignant and malignant tumors will also be evaluated. We will compare the results of topical application studies with those from experiments with oral administration to determine possible mechanistic differences between the two modes of administration.
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