Retinoids as cancer-preventive agents

Vitamin A and its metabolites play a crucial role in regulating the differentiation and proliferation of epithelial cells, and are potent inducers of apoptosis. The effects of retinoids are thought to be mediated through the metabolite retinoic acid, which binds to nuclear retinoic acid receptors that then interact with specific retinoic acid response elements. The development of cancers involves alterations in growth and differentiation of cells as a result of carcinogen-induced damage to DNA of regulatory genes. Most of the results from experimental animal studies indicate that retinoids are effective in preventing or suppressing cancers. Although the relationship between preformed vitamin A in the diet and epithelial cancers remains to be further clarified, a high intake of vegetables and fruits has been consistently associated with a lower risk of these cancers. This interesting biological activity profile of retinoids has prompted investigators to study them in the chemoprevention of epithelial cancers and in the treatment of advanced cancers. Although the therapeutic response of retinoids against advanced cancers is disappointing, they have emerged as promising chemopreventive agents, particularly in head and neck sites. Both natural and synthetic analogues of vitamin A have been shown to be effective in suppressing micronucleated cells, reversing oral leukoplakia, and preventing new and recurrent lesions in subjects with oral leukoplakia, as well as in reducing the occurrence of second primaries in treated head and neck cancer patients. They have not been consistently effective in suppressing either bronchial atypia or metaplasia, nor have they been proven effective in reducing the occurrence of recurrent lesions in treated skin cancer patients, although some activity has been demonstrated in reducing lesion counts in actinic keratoses. Vitamin A in combination with other micronutrients has not reduced incidence and mortality from oesophageal and stomach cancers. A synthetic retinoid, fenretinide, is currently being evaluated in preventing contralateral breast cancer in treated breast cancer patients. Toxicity has been a major concern with retinoids, as prolonged administration is required in chemoprevention studies. Available evidence indicates that natural analogues of retinoids are less toxic than synthetic compounds such as isotretinoin. Large studies are currently evaluating retinoids in the prevention of head and neck cancers and lung cancers. The outcome of these studies will be important in directing future research initiatives and in forming policies regarding the use of vitamin A compounds in the prevention of cancers.