INTRODUCTION
As early as the 1960s, topical tretinoin demonstrated clinical potential in a variety of skin disorders,
including acne, actinic keratoses, other hyperkeratotic conditions, and antitumor effects in a number of basal cell cancers. Since then, other uses have been described, including
the treatment of lesions of the oral mucosa and the ocular surface epithelia, hypertrophic scarring, various infections, and pigmentation disorders.1,2
Kligman and colleagues3 at the University of Pennsylvania reported on
the effectiveness of topical tretinoin in treating acne in 1969. In 1971, tretinoin became the first retinoid to be approved by the US Food and Drug Administration (FDA) as a topical treatment for acne vulgaris (AV).4,5
Soon after topical tretinoin became available to the public,
elderly patients using it to treat acne reported noticing a general improvement in the condition of their skin.6 Considering this, Kligman and colleagues began trials to study the
use of topical tretinoin in treating photodamaged skin. Beneficial results were subsequently verified by large multicenter trials and clinical experience supporting the efficacy and
safety of topical tretinoin to treat photodamaged skin.6 In 1995, topical tretinoin
was approved by the FDA for the palliation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial photodamage.7
The aim of this review is to provide an overview of the history and current uses of topical tretinoin, including likely mechanisms of action, approved indications and dosing, and associated safety and tolerability issues, as well as to speculate on potential therapeutic areas that may be targets for further research and future clinical applications.
Clinical Chemistry, Pharmacology, and Mechanisms of Action
Tretinoin (all-trans retinoic acid) is a retinoid metabolite of naturally occurring vitamin A that activates 3 nuclear retinoic acid receptors (RARα, RARβ, and RARγ). These receptors can act to modify gene expression, protein synthesis, and epithelial cell growth and differentiation.8,9 Tretinoin may exert its clinical effects, at least in part, through activation of retinoid receptors; however, its exact mechanisms of action are unknown.8,10 The binding profile of tretinoin differs from that of synthetic retinoids, such as adapalene, which binds preferentially to RARβ and RARγ, and tazarotene, which binds to all 3 RARs but appears to lead to an effective gene expression only via RARβ and RARγ.11
Topical tretinoin has the ability to modify abnormal follicular keratinization and promote comedolysis, modulate the proliferation and differentiation of epidermal cells, stimulate the formation of new collagen, reduce inflammation, stimulate fibroblasts, prevent collagen loss, and inhibit the induction of skin metalloproteinases (ie, collagenase, 92-kd gelatinase, and stromelysin, which are induced by ultraviolet [UV] irradiation and may degrade skin collagen).8,10,12-15 In addition, tretinoin decreases epidermal melanin, as measured by Fontana Masson staining,15,16 and may
