Chemoprevention of cancer with retinoids

Abstract

Retinoids are defined as that group of molecules consisting of vitamin A and its natural and synthetic derivatives. Approximately 1500 different retinoids have been synthesized by modifying either the ring structure, the side chain, or the terminal group of the molecule. To date, however, only two synthetic retinoids, isotretinoin (13cis-retinoic acid, RO-4-3780, Accutane) and an aromatic retinoid (etretinate, RO-10-9359, Tigason) (Fig. 1) have been used in clinical trials, primarily for dermatologic disease. For the past 40 years dermatologists have used oral vitamin A as therapy for a variety of dermatoses. This usage was based initially on the similarity between the follicular keratoses seen in vitamin A deficiency and those in previously treatment-resistant skin disorders, such as Darier’s disease (keratosis follicularis) and pityriasis rubra pilaris. Once beneficial effects of oral vitamin A were observed, its use spread to the treatment of other diseases of the epidermis and epidermal appendages, ranging from acne to psoriasis to basal cell carcinoma. More recently, topically applied retinoic acid has been similarly studied. Since the hypervitaminosis A syndrome interfered with long-term therapy with vitamin A, the need arose for synthetic derivatives which could be at least as efficacious as vitamin A and yet be less toxic. In 1976, when isotretinoin first became available for clinical testing in the United States, clinical testing began at the Clinical Center, National Institutes of Health, with the treatment of cystic acne, cutaneous disorders of keratinization, and basal cell carcinoma. In 1978, etretinate also became available for clinical trials in this country after several years of trials in Europe primarily in the treatment of psoriasis. These synthetic retinoids were found to be more effective and less toxic than vitamin A [I ,2]. A spectrum of disease-specific responses was observed between isotretinoin and etretinate. Isotretinoin was far more effective in cystic acne and acneiform disorders, such as rosacea and hidranenitis suppuritiva. Etretinate was more effective in psoriasis and other disorders of keratinization, such as epidermolytic hyperkeratosis, X-linked ichthyosis, ichthyosis vulgaris, and keratoderma palmaris et plantaris. Other disorders of keratinization such as Darier’s disease, chronic pityriasis rubra pilaris, and lamellar ichthyosis responded similarly to both retinoids [3]. In cystic acne prolonged remissions after discontinuation of