) Non-melanoma skin cancer (NMSC) is the most common type of human cancer and epidemiological evidence strongly implicates ultraviolet radiation in sunlight as the major cause of this form of malignancy. The most common type of NMSC is basal cell carcinoma (BCC) and there are two major types of BCC, those occurring sporadically and those that develop in patients with the genetic disorder known as the basal cell nevus syndrome (BCNS). Sun exposure is a crucial factor in the development of BCC in both populations and recent studies have shown that mutations in the human homologue of the Drosophila segment polarity gene PATCHED (PTC) occur in patients with BCNS and in patients with sporadic BCCs. In this project we plan to conduct a series of studies in SKH-l hairless mice, in patched gene knockout mice (ptc +/-) and in human volunteers to test the hypothesis that systemic administration of the chemopreventive agents, Polyphenone E, a mixture of constituents of green tea, Sulindac, an inhibitor of cyclooxygenase (COX) I and 2 and Celecoxib, an inhibitor of COX 2 can diminish the phototoxic response to ultraviolet B (UVB) and psoralen-ultraviolet A (PUVA) in the skin. Minimal erythema dose (MED) to UVB and minimum phototoxic dose (MPD) to PUVA will be employed to induce a localized phototoxic response in the skin of the animals and the human subjects and the ability of the systemically administered chemopreventive agents to protect against these responses determined. Surrogate biological markers of cancer risk including erythema and edema, apoptosis, c-jun, c-fos and ras p21 induction, BrUdr incorporation, proliferating cell nuclear antigen (PCNA) expression and epidermal growth factor (FGFR) phosphorylation will be assessed. Tumor studies in the animals will permit direct comparison of the susceptibility of the mouse strains to UVB induced tumors and the ability of the chemopreventive agents to reduce the risk of cancer. These studies are closely integrated with those in Projects 1 and 2 and will generate strong supportive data that can be correlated with the findings from those studies. This combined approach has the unique potential to more frilly define the anticarcinogenic effects of selected chemopreventive agents in human populations and to further characterize their mechanism of action.
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