This comprehensive program is for the design, synthesis, and evaluation of new retinoids as potential chemopreventive agents. To select, from all that are prepared, retinoids with the greatest chemopreventive potential, the compounds will be evaluated initially in biochemical and organ culture systems and in systems designed to measure their immunological properties. Those selected will be tested in vivo for their effect in preventing skin papillomas, bladder cancer, and mammary carcinomas. For compounds having considerable activity in one or more of these systems, pharmacological and toxicological studies will be performed. The results of these studies, with observations on the structure-activity relationships, will be used to guide the synthesis program in the design of new compounds and to select candidates for clinical investigation. Research projects, each relating to the mechanism of action of retinoids, concern (a) early events associated with the binding and uptake of retinoids and with tumor promotion; (b) the function of retinoic acid binding proteins; (c) the relationship between disposition and chemopreventive activity of retinoids; (d) evaluation of the effects of retinoids on immune function; and (e) synthesis of new retinoids having potential chemopreventive activity, but little toxicity. The development of new, more effective, and less toxic retinoids would offer hope of therapy to those who have been or will be exposed to substantial quantities of carcinogens and to others determined to be at high risk for cancer.
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