EVALUATION OF CHEMOPREVENTIVE AGENTS USING A TRANSGENIC MOUSE MELANOMA MODEL

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We have developed transgenic mouse lines that are susceptible to the development of melanoma. These mice provide a model system for evaluating chemopreventive agents because they exhibit the necessary characteristics: a high incidence of tumor development, a moderate latency period and progressive stages of tumor development. We have demonstrated that the chemical carcinogen, 7, 12-dimethylbenz[a]anthracene and the environmental carcinogen, UV irradiation (280-340 nm), will cause melanoma in the TPras transgenic mice. The melanoma from DMBA-treated mice exhibit genetic and chromosomal alterations similar to those described for human melanomas. Using TPras transgenic mouse lines as our models, we propose to test the hypothesis that certain chemopreventive agents will prevent DMBA- and/or UV-induced melanoma by protecting against DNA damage or modulating the ras signaling pathway. Activation of upstream and downstream events in the ras pathways have been demonstrated as necessary for proliferation of melanocytes. In addition ras mutations have been observed in about 25% of the melanoma that developed in sun-exposed sites. The specific aims that will be pursued to address our hypothesis are: 1) to evaluate the effects of retinoids (tretinoin, panretinin), perillyl alcohol (PA), epigallocatechin gallate (EGCG), and alpha-difluoromethylornithine (DFMO) on melanoma development in the Tpras transgenic mouse models. We will asses the effect of preventive agents on development of premalignant lesions, tumors, latency period, size and number of tumors, and metastatic spread; 2) To study which chemopreventive agents may prevent or block UV- induced DNA damage in melanocytes. In particular, we will examine the effects of the above agents on formation of pyrimidine dimers and the generation of reactive oxygen species; and 3) To investigate the effects of retinoids, PA, and DFMO in UV-induced epigenetic effects in melanocytes, specifically activation of the ras pathway. We will monitor activation/farnesylation of G-proteins, and AP-1 activity. Biological activities in melanocytes associated with activation of the ras pathway include proliferation as well as induction of apoptosis. These preclinical studies are designed to lead to the development of new chemopreventive strategies for human melanoma skin cancers.