EVALUATION OF CHEMOPREVENTIVE AGENTS USING A TRANSGENIC MOUSE MELANOMA MODEL

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Malignant melanoma is a very aggressive disease which shows a high propensity for metastatic spread. Treatment is problematic because it is very resistant to most chemotherapeutic regimens. its incidence is increasing more rapidly than any other malignancy except lung cancer. At the current rate by the year 2000, 1 out of every 100 Americans will develop melanoma (l; 2). There is little doubt that exposure to the ultraviolet B radiation present in the solar spectrum contributes to development of the disease. There is a need for mechanistic studies as well as intervention studies, including prevention and treatment strategies, of malignant melanoma. The lack of an animal model in which the tumor can be reproducibly induced with a short latency period has hampered efforts to develop and evaluate experimental therapeutic and prevention agents. We propose a solution to this problem would be a transgenic mouse model in which the expression of an oncogene or protooncogene is directed in a cell specific manner to melanocytes. We have prepared minigene constructs with a mutated human Ha-ras gene and a v-jun oncogene driven by melanocyte-specific regulatory elements, the tyrosinase promoter. The expression of the transgene would be equivalent to tumor initiation in the melanocytes. Tumor promoters and ultraviolet light exposure of the initiated animals would then provide the events necessary for tumor promotion and progression. A multistage mouse model of melanoma development would thus provide a system to study the efficacy of potential chemopreventive agents.