DESCRIPTION: (Applicant's Abstract) Non-melanoma skin cancer is an increasingly prevalent disease. One out of every six Americans will develop skin cancer in his or her lifetime, and over 700,000 new cases of skin cancer will be diagnosed in the United States this year. Selenium (Se) is an essential trace element with a Recommended Dietary Allowance of 70 ug/day for male adults. Low plasma Se levels have been linked to increased risk of non-melanoma skin cancer and baseline Se levels may be predictive of future skin cancer risk. A recent intervention trial in human skin cancer patients demonstrated no efficacy of selenomethionine against the recurrence of basal cell and squamous cell carcinomas, although there was a decrease in incidence of lung, colon and prostate cancers. However, previous work from the applicant's laboratory has demonstrated a protective effect of Se as selenite for ultraviolet light B (UVB)-induced skin tumors and protection against the UVB-induction of oxidative lesions in the DNA of cultured keratinocytes. The hypothesis to be tested in this application is that the efficacy of Se chemoprevention is dependent on the form of Se used, and this efficacy is determined by the relative contribution of the compound to Se's antioxidant or prooxidant properties. To test this hypothesis, the applicant plans to 1) determine the relative efficacy of selenium compounds to induce the antioxidant pathway by glutathione peroxidase, and also the ability to induce the prooxidant, apoptotic pathway in cultured human keratinocytes and squamous cell carcinoma cells; 2) to determine if there is an interaction between Se compounds and glutathione and other antioxidant compounds; 3) to determine if the antioxidant and prooxidant effects seen in vitro also occur in vivo in the mouse model of skin cancer; and 4) to determine if there are differing chemoprevention capabilities based upon the hypothesized prooxidant mechanisms in a mouse model of skin cancer; and 5) to delineate the molecular mechanisms for the efficacy of Se compounds in skin cancer prevention based on the timing of p53 mutations and their modulation by different Se compounds. The applicant hopes to understand from these experiments which Se compound will be most effective, when and why, in terms of non-melanoma skin cancer prevention.