This comprehensive program is for the design, synthesis, and evaluation of new retinoids as potential chemopreventive agents. To select retinoids with the greatest potential, the compounds are evaluated initially in biochemical systems and in systems designed to measure their effect in enhancing immunological responses. Those selected, on the basis of high activity in these tests, are evaluated, as appropriate, in intact animals for their effect in preventing skin papillomas, Moloney virus-induced lymphomas, and/or mammary carcinomas. For compounds having substantial activity in one or more of these systems, pharmacological and toxicological studies are performed. Results of these studies, with observations on the structure-activity relationships, are used to guide the synthesis program in the design of new compounds and to select candidates for clinical investigation. Development of new, less toxic retinoids offers potential therapy to individuals who are at high risk for developing cancer. Research projects concern (a) synthesis of new conformationally restricted retinoids with potential biological activity; (b) evaluation of the effects of retinoids on immune function; and (c) synthesis of new retinoids related in structure to those with known chemopreventive activity and little toxicity. The core components deal with (a) preparation of large amounts of retinoids for biological evaluation, (b) evaluation in mice of compounds designed to prevent skin cancer, (c) the pharmacological and toxicological properties of retinoids, (d) evaluation in rats of compounds designed to prevent mammary cancer, (e) the binding of retinoids to various binding proteins and receptors, and (f) statistical evaluation and program administration. Developmental and interactive research is conducted in both the research projects and core components.
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