RETINOIDS AND CHEMOPREVENTION OF AERODIGESTIVE TRACT CANCERS

Natural and synthetic vitamin A metabolites and analogs (retinoids) we re found to suppress head and neck and lung carcinogenesis in animal m odels and inhibit carcinogenesis in individuals with premalignant lesi ons and a high risk to develop cancer of the aerodigestive tract. Like wise, retinoids prevent the development of second primary cancers in h ead and neck and lung cancer patients who had been treated for the fir st primary. These effects are thought to result from changes in the ex pression of genes that regulate cell growth and differentiation. Most of the effects of retinoids on gene expression are mediated by nuclear retinoic acid receptors RARs (alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma), which function as retinoid-act ivated transcription factors. Like vitamin A deficiency, alterations i n receptor expression or function could interfere with the retinoid si gnaling pathway and thereby enhance cancer development even in vitamin A sufficient individuals. We found that the expression of RAR beta wa s suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer (e.g., oral leukoplakia and squamous metap lasia), in dysplastic lesions adjacent to cancer, and in malignant ora l and lung carcinomas. The expression of the other receptors was not d ifferent among normal, dysplastic, and malignant oral tissues. However , the expression of RAR gamma and RXR beta was somewhat decreased in l ung cancers. These results show that RAR beta expression is lost at ea rly stages of carcinogenesis in the aerodigestive tract and support th e hypothesis that the loss of RAR beta expression may facilitate the d evelopment of some of these cancers.