GENISTEIN IN INVESTIGATIVE AND CLINICAL DERMATOLOGY

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DESCRIPTION: (applicant's description) This application proposes to test the hypothesis that genistein, a soybean isoflavone, inhibits ultraviolet radiation {UVR)-induced pyrimidine dimers and oxidative DNA damage, and modulates UVR activated signal transduction cascades, thereby suppressing the initiation and promotion of photocarcinogenesis. The first aim of the project is to determine if pre- or post-application of genistein prevents UVR-induced skin carcinogenesis. Genistein will be topically applied to hairless mice during exposure to UVR. The protective efficacy will be evaluated by analyzing the latency period, tumor incidence and multiplicity. The second aim is to evaluate the effect of genistein on initiation, promotion, and progression of UVR-induced skin carcinogenesis. Genistein will be topically applied to mouse skin before an initiating dose of UVR, followed by TPA promotion, or applied before UV irradiation in DMBA initiated mouse skin. UVR-chemical combination models will be used to dissect the anti-initiation or anti-promotion effects of genistein on the UVR exposure. The anti-progression effect will be evaluated by applying genistein to existing cutaneous tumors and recording the tumor regression and malignant conversion rate. The third aim is to examine if genistein inhibits UVR-induced intermediate endpoints relevant to initiation and promotion, e.g. DNA photoproducts, oxidative DNA damage, inflammatory responses, ornithine decarboxylase (ODC) induction and protooncogene expression in vivo. The fourth aim is to further elucidate the molecular mechanism(s) whereby genistein inhibits photocarcinogenesis in vitro. The effect of genistein on UVR-induced activation of tyrosine protein/mitogen activated protein kinases, phosphorylation of the epidermal growth factor receptor as well as activation of the AP-1 transcription factor in murine and human keratinocytes will be examined. Lastly, the applicant will evaluate the efficacy of genistein in protection of UVR-induced erythema and discomfort in the skins of human subjects. In addition, certain molecular endpoints such as 8-OHdG, pyrimidine dimers, p53 and proliferating cell nuclear antigen (PCNA) expression will be detected in human skin biopsies and the reconstituted 3-dimensional human skin. Successful completion of the proposed studies will contribute to development of this soybean isoflavone as a preventive and/or therapeutic agent against human skin cancer and photodamage.