Vitamin A and Its Derivatives in Experimental Photocarcinogenesis: Preventive Effects and Relevance to Humans

April 2013 | Volume 12 | Issue 4 | Original Article | 458 | Copyright © 2013

Stanley S. Shapiro PhD,a Miri Seiberg PhD,b and Curtis A. Cole PhDc

aSkinnovations, LLC, Roseland, NJ
bSeiberg Consulting, LLC, Princeton, NJ
cJohnson & Johnson Consumer Companies, Inc, Skillman, NJ

Abstract

The 1925 classical observation that vitamin A deficiency leads to squamous metaplasia and epithelial keratinization, coupled with the later finding that excess vitamin A inhibits keratinization of chick embryo skin, set the foundation for the potential therapeutic use of retinoids in cutaneous conditions of keratinization. Significant progress has since been made understanding the molecular biology, biochemistry, pharmacology, and toxicology of vitamin A and its derivatives, collectively named retinoids. Natural and synthetic retinoids are now routinely used to treat acne, psoriasis, skin keratinization disorders, and photodamage. Retinoids also inhibit tumor formation and skin cancer development in experimental systems and in humans. Retinol and retinyl palmitate (RP) are found in cosmetic products and in foods and dietary supplements, which are all considered safe, by inclusion in the Generally Recognized as Safe Substances Database. However, the safety of topical retinoids was questioned in one publication and in a recent National Toxicology Program report of RP-containing topical preparations, suggesting the possible earlier onset of ultraviolet-induced squamous cell carcinomas in the hairless mouse photocarcinogenesis model. This suggestion contradicts a large body of data indicating that topical retinoids are chemoprotective in humans, and it was immediately challenged by new reviews on the safety of RP in general and within sunscreens. This paper will review the preclinical and clinical data supporting the safety and chemopreventive activity of retinoids, with an emphasis on RP, and will examine the experimental systems used to evaluate the safety of topical vitamin A preparations in order to provide perspective relative to human skin.

J Drugs Dermatol. 2013;12(4):458-463.

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INTRODUCTION

Retinoids in Experimental Models for Cancer Prevention

Retinoids are active in the prevention of numerous types of cancers in experimental model systems,1 with skin cancer data derived mainly from the 2-stage mouse carcinogenesis model.2 In this model, an initiating dose of a carcinogen is applied to the animal skin, followed by repeated doses of a promoting agent, resulting in the formation of skin papillomas and carcinomas. For example, topical retinyl acetate reduced tumor incidence up to 75% in a 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)–promoted carcinogenesis model.2 Similarly, retinoic acid (RA) and its metabolite 5,6-epoxy-RA as well as topical 13-cis-RA inhibited tumor promotion in this model.3,4 Interestingly, oral 13-cis-RA failed to reduce tumor number and tumor yield in this model system but did reduce tumor size.5 In a dietary study, retinyl palmitate (700,000 IU/kg diet for 5 weeks followed by 350,000 IU/kg of diet) led to a 65% decrease in TPA-induced papilloma yield, whereas oral 13-cis-RA (700,000 IU/kg/g) reduced only tumor size but not tumor number.6 High dietary levels of RA (30 μg/d) also inhibited mezerein-induced tumor promotion and malignant transformation.7 While the vast majority of the 2-stage model studies document retinoids as inhibitors of tumor promotion, a single study using the same model system8 showed that RA (5.1 mg, topically applied 3 times/wk for 20 weeks) was a weak promoter in DMBA-initiated carcinogenesis.

Oral Retinoids in Human Skin Cancer Prevention

Oral retinoids acts as chemopreventive agents in numerous human cancers, including the skin.9,10 Clinical trials11-18 had evaluated several oral retinoids (eg, isotretinoin, etretinate, acitretin) in the prevention of nonmelanoma skin cancer (NMSC), with a documented trend of chemoprevention. These clinical studies also include extremely high-risk populations for skin cancer development, such as xeroderma pigmentosum (XP) patients who lack the ability to repair ultraviolet (UV)-induced DNA damage and organ transplant patients who are immunosuppressed. In 1 XP study,13,14 a high dose of oral isotretinoin (2 mg/kg/d) led to a 63% reduction in new skin cancers following 2 years of treatment. Upon discontinuing daily isotretinoin, the frequency of skin cancer in the posttreatment year increased 8.5-fold. In renal transplantation patients,11,16 acitretin (30 mg/d) led to a significantly lower number of patients with new skin tumors as well as to a lower total number of tumors compared with the placebo group. Oral retinol and isotretinoin dose-dependently increased the time to first appearance of NMSC in high-risk individuals, with the exception of the lowest dose, which showed

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