Retinoids in chemoprevention of cancer

Retinoic acid (RA), a natural metabolite of circulating Vitamin A (retinol) and an irreversible oxidation product of retinol, is essential in maintaining the normal pathway of differentiation of epithelial tissues. RA and a number of its analogs, both natural and synthetic (retinoids), have been shown to be effective in the prevention of a variety of cancers in experimental animals, and in reversing preneoplastic lesions in humans. The retinoids exhibit a high degree of specificity in cancer chemoprevention. Diverse effects of retinoids are mediated by retinoid nuclear receptors, the ligand-inducible trans-acting transcription factors. The receptor-selective retinoids may be more effective and less toxic in cancer prevention. Our chemoprevention study with retinoids using the mouse skin carcinogenesis model indicated that retinoids are anti-tumor promoters. One of the mechanisms by which retinoids inhibit promotion of mouse skin tumor formation involves their property to inhibit the induction of ornithine decarboxylase by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate. RARalpha and RARgamma, but not RXRs, may mediate mouse skin anti-tumor promotion activity of retinoids. Retinoids are highly selective chemopreventive agents and are toxic at high pharmacological doses. Clinical trials with retinoids should be conducted with a carefully evaluated, appropriate patient population and perhaps at low doses in combination with other chemopreventive agents with mechanisms of action different from retinoids.