Parenteral retinoid administration will be used to explore several aspects of retinoid modulation of epithelial carcinogenesis to elucidate the anti- carcinogenesis properties of retinoids in long-term attempts to understand mechanisms of abnormal differentiation. The model meets criteria of critical importance in the potential retinoid responsiveness of cells, namely, it achieves local tissue levels, without the systemic toxicity observed following conventional administration, with physiologic rather than pharmacologic doses of the natural retinoid, retinyl palmitate, which can be hydrolyzed to the reported physiological effective retinoid, retinol. The objective of the present proposal, which is an extension of previous studies, is to evaluate natural and synthetic retinoids of differing chemical structure for their absolute and relative ability to inhibit or reverse chemically-induced (7,12-dimethylbenz (a) anthracene; DMBA) epithelial skin tumors and to identify mechanism(s) of action of retinoids by determining whether their effects are by cell selection or phenotype modulation. Light and electron microscopy, radiobiochemistry, and autoradiography, methods are used to evaluate lesions before and after retinoid treatment. It is anticipated that this research will provide experimental evidence for basic mechanisms of abnormal differentiation and modulation by retinoids. The retinoid work is significant in that it represents a physiologic rather than cytotoxic approach to chemoprevention of carcinogenesis in epithelia that account for more than one-half of the total primary cancer in men and women.
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