METABOLISM OF CHEMOPREVENTIVE RETINOIDS

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Retinoids are potent anticarcinogenic agents which inhibit the formation of carcinogen induced preneoplastic lesions (hyperplasia, squamous metaplasia) and cause regression of preformed lesions in epithelial tissues. 13-cis-Retinoic acid has demonstrated potent chemopreventive activity coupled with diminished host toxicity in animal studies. 13-cis-Retinoic acid is currently undergoing clinical trials in individuals who are at identifiable high risk for development of epithelial cancers. The prospect for long-term administration of this retinoid necessitates a detailed investigation of its in vivo metabolism. Furthermore, the consequences of chronic 13-cis-retinoic acid therapy on the physiological metabolism of endogenous retinoids must be evaluated. We propose to establish a rat model of chronic 13-cis-retinoic therapy and to use this model to study the in vivo metabolism of this retinoid. The objectives of the proposed research are: 1) the investigation of the metabolites of 13-cis-retinoic acid in selected retinoid target-tissues of chronically treated rats; 2) the characterization of the chemical structure and anticarcinogenic activity of these metabolites and 3) the evaluation of the effects of chronic 13-cis-retinoic acid treatment on certain aspects of phy siological retinol metabolism. Metabolism studies will be conducted with high-performance liquid chromatography (HPLC) methods developed by the authors for the separation of retinoids. The individual in vivo metabolites of 13-cis-retinoic acid will be purified by HPLC and identified by absorbance spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy, an chemical synthesis. The anticarcinogenic activity of the metabolites will be tested in two retinoid-sensitive assays: the epidermal ornithine decarboxylase assay and the embryonal carcinoma differentiation assay. Information gained from the correlation of metabolite structure with anticancer activity would not only help to delineate the in vivo metabolism of 13-cis-RA, but could provide insight useful for the design of synthetic retinoids with enhanced chemopreventative activity, increased biological half-lives, and perhaps selective localization. Three important aspects of vitamin A homeostasis will also be investigated in 13-cis-retinoic acid treated rats; liver vitamin A stores, serum retinol levels, and the steady-state concentrations of retinyl esters, retinol, and tetinoic acid in several vitamin A-target organs. These experiments will be used to pobe the effects of chronic 13-cis-retinoic acid therapy on the metabolism of endogenous retinoids.