Retinoids and cancer.

The synt hetic retinoids represent a new class of drugs wh ich a re highly effective in t he treatment of a broad spectrum of dermatologic d isease, including cystic acne, psori asis, and cutaneous di sorders of keratinization [1 3]. Moreover, t he use of synthetic retinoids in cancer prevent ion and therapy fo r both cutaneous and in te rna l t umors is potent ially the most signi ficant clinica l use of t hese dru gs. Vitamin A de!iciency may provide a conceptua l link in un derstanding how retinoids may be effective as t herapy fo r benign dermatoses and be of value in t he treatment and prevention of skin ca ncer. One characteristic feature of vi ta min A defi ciency is a squamous metaplasia of a variety of epit helia, including t he t rachea, cornea, urina ry bladder, pa rotid gland , p rostate, and ute rine cervix l4) . Increased cell proli fe ration and hyperkeratosis a re features of both squamous metaplas ia and some benign dermatoses, for example, psoriasis. S imilarly, fo llicular hyperkeratosis is seen both in vita min A defi ciency and in acne, keratosis follicul aris and pityriasis rubra pila ris. The findin g t hat retinoids rapidly reverse t he squamous metaplasias induced by both vi tamin A deficiency and by carcinogens supports t he concept t hat retinoids may be of va lue in cancer chemoprophylax is. Furt hermore, vitamin A defi ciency may be a precancerous disease. For example, vitamin A deficiency in t he rat enhances t he susceptibility of t he respi ratory t ract, bladder, and colon to experimenta l carcinogenesis. I n humans, epidemiologic studies have assoc iated t he incidence of cancer with decreased se rum retinol [5]. During t he past 10 years, in practical demonstration of t he above concept, several retinoids have been used in a nimals a nd h umans in t he treatment or prevent ion of skin tumors. Ini t ia lly, tretinoin (all -transretinoic ac id) was used both topically and systemically. More recent ly, isotretinoin (13-cisretinoic acid) a nd aromatic derivat ives of retinoic acid (etretinate) and retin oidal benzoic acid derivatives (arotinoids) have been demonstrated to be more effective and less tox ic t han t retinoin in t he t reatment of skin diseases, including tumors [1 3,6]. Moon and I t ri suggest t hat t here a re several a reas where r etinoids may prove useful in clinical oncology: (1) for t reatment of advanced disease, (2) for t reatment which is adjuvant to other ant icancer therapy, (3) for reversal or different iation of preneoplastic les ions, (4 ) for prevent ion of cancer in highr isk populations, and (5) for t he prevent ion of cancer in t he general population [7]. The synthetic retinoids, isotretinoin and etretinate, have been used in t he t reatment and prevent ion of cutaneous malignancy in patients wi t h mul t iple basal cell carcinomas due to chronic sunlight exposure, t he nevoid basal cell carcinoma syndrome, or xeroderma pigmentosum; mult iple actin ic keratoses; mul t iple keratoacanthomas (Ferguson-Smit h); so litary la rge keratoacanthomas; porokeratosis of Mibelli wi t h malignant degeneration (squamous cell carcinoma, Bowen's disease); malignant eccrine poroma; epidermodysplasia verruciformis; o ral leukopla ki a; cutaneous metastases of malignant melanoma a nd cutaneous T -celllymphoma (mycosis fun goides and Sezary syndrome) [ 1,2,6]. Aside from t he actinic keratoses, t he soli tary keratoacanthomas, and approximately 10% of basa l ce ll carcinomas, t he synt hetic retinoids usually do not cure cutaneous tumors but do produce va riable degrees of part ia l regression when give n at high dosage. P recancerous diseases in organs other t han t he skin also h ave been reported to respond to retinoids. T wo placebo-con-