EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS IN ANIMAL MOD

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In view of the relatively high and increasing prevalence of nonmelanoma skin cancer, the development of animal models for testing potential chemopreventive agents is urgent. In fact a model of UV-induced skin carcinogenesis in mice has existed for at least 20 years. This is the SKH (hairless mouse). This mouse strain is hairless due to the insertion of a retrovirus at the "haired" locus on chromosome 14. In homozygous recessive mice UV exposure induces skin carcinomas and precursor lesions (e.g. atypical hyperplasias and carcinoma in situ) from the epidermis. This study examines the effects of chemopreventives primarily on tumor morphological endpoints however we are examining a more limited number of potential surrogate endpoint biomarkers for their modulation by these agents. Endpoints include: A) Various cell cycle regulated proteins i.e. cyclins and their related kinases. e.g. Cyclin D1 B) Measures of DNA synthesis(BudR or PCNA) ; C) Telomerase . These endpoints lend themselves to quantitative analysis. 1) To employ the SKH hairless mouse model to examine three agents starting chemopreventive treatment either immediately prior to following or 10 weeks following treatment with the agents. These agents ( 2 methoxy estradiol, iNOS inhibitor, NSAID, and DFMO) will all be administered in feed; 2) To employ only two of the effective agents to determine whether they can modulate expression of potential biomarkers (e.g. cell cycle proteins (e.g. PCNA),cyclin levels and telomerase activity).