Retinoids in Cancer Chemoprevention

Vitamin A and its analogues, the retinoids, are known to play a major role in tissue differentiation, as well as in cellular growth and maturation.' However, their poor tolerability in humans has always limited the use of these compounds to few medical indications, mainly in dermatology (e.g., treatment of psoriasis). Vitamin A is SO extensively involved in a number of different biological processes that its long term 01 high dose intake can lead to a great variety of side effects and unfavorable events: most of them are reversible and usually disappear within a few hours or days after drug withdrawaL2 Because retinoids, both natural and synthetic, have been repeatedly proposed as cancer chemopreventive agents due to their differentiating properties, the issue of their tolerability and safety in humans has to be addressed. The encouraging clinical results obtained with isotretinoin in reducing the occurrence of second primary tumors in patients previously treated for squamous-cell carcinoma of the head and neck3 stressed once again the need for less toxic and more effective synthetic analogues of vitamin A: one-third of the patients receiving isotretinoin did not complete the 12-month course of treatment because of toxicity or noncompliance. From the dermatological standpoint, the main side effects of retinoids are mucocutaneous dryness, skin atrophy, and skin ~ulnerability.~ Abnormal cutaneous photosensitivity has also been reported for some vitamin A synthetic analogues5 and severe nail dystrophy has been described.6 As far as the eye is concerned, retinoids can induce conjunctivitis on one side, but also interfere with some mechanisms of vision and in particular with dark adaptation.' In the rod outer segment of the retina, rhodopsin is catalyzed into opsin and retinal by the light and this reaction leads to the generation of the nervous impulse that goes to the brain to activate the mechanism of vision. The retinal only converts into retinol and vice