PRECLINICAL EVALUATIONS OF INTERMEDIATE ENDPOINTS

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The objective of this project is to determine the mechanism of action of 4HPR, retinyl acetate and 9 cis retinoic acid. N-methyl-N-nitrosourea (MNU) is being used to generate mammary tumors in Sprague-Dawley rats. The animals are being exposed to the three retinoids (9-cis retinoic acid, 4 HPR, and retinyl acetate) for six weeks. Individual livers, mammary glands, and lungs are examined for the expression of the RNAs coding for RAR alpha, RAR beta , RXR alpha and one other gene which is modulated by retinoids. Mammary tumors from rats treated with MNU-alone or rats treated with MNU plus retinoid are used to determine the long term effects of the retinoids on tumor tissues. The levels of apoptosis in these tissues are being measured employing standard published techniques for measuring apoptosis. The genetic changes associated with mammary tumorigenesis in rodents and humans are being examined. Liver samples are also being studied to determine whether potential markers on the rat genome display heterozygosity at the specific sites to be examined. Mammary tumors and a more limited number of "normal" regions of breast tissue are being examined for loss of heterozygosity in regions syntenic to the human 7Q region in these animal tumors. DMBA -induced tumors from Fl mice are also being examined for the loss of the region syntenic to the human 7Q region.