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The retinoic acid paradox in cancer chemoprevention.

Journal of the National Cancer Institute, Vol. 98, No. 7, April 5, 2006 Decades of basic scientifi c studies and initial clinical trials have indicated a potential role for the classical retinoids in cancer chemoprevention ( 1 ) . Indeed, the concept of clinical cancer chemoprevention is based largely on preclinical and early clinical studies in which retinoids suppressed epithelial carcinogenesis ( 2 – 5 ) . However, in a recent randomized phase III intergroup chemoprevention trial, the retinoid isotretinoin did not reduce second primary tumor formation, recurrences, or mortality in patients with stage I non – small-cell lung cancer ( 6 ) . And in this issue of the Journal, Khuri et al. ( 7 ) report results of a rigorously conducted placebo-controlled phase III trial showing that isotretinoin was not effective in mediating chemoprevention in pa tients with early-stage head and neck squamous cell carcinoma (HNSCC). It is now important to uncover the basis for this paradoxical lack of isotretinoin clinical chemoprevention activity. Answers will likely come from a more complete understanding of the molecular mechanisms and pharmacology of retinoids. Retinoids comprise natural and synthetic derivatives of vitamin A that regulate many essential biologic functions. Retinoids activate transcription by binding to nuclear receptors. Isotretinoin, also known as 13cis -retinoic acid, is converted to alltrans -retinoic acid, which activates the classical nuclear retinoic acid receptors (RARs), whereas 9cis -retinoic acid activates both the RARs and the nonclassical nuclear retinoid X receptors (RXRs). RARs can heterodimerize with RXRs, whereas RXRs heterodimerize with other nuclear receptors, including the thyroid hormone receptor, the vitamin D receptor, and peroxisome proliferator – activated receptors ( 8 ) . Novel synthetic retinoids, including RXR-selective agonists termed “ rexinoids, ” have recently shown promising clinical activity in a combination regimen that targets non – small-cell lung cancer ( 9 ) . Because RXRs form heterodimers with nuclear receptors that affect lipid physiology, their effects are also being investigated in other medical conditions, including the metabolic syndrome, which is characterized by obesity, dyslipidemia, diabetes, and hypercoagulability ( 8 ) . The retinoid-signaling pathway was studied in normal and neoplastic tissues to identify why preclinical retinoid activity did not readily translate into clinical success. It was discovered that expression of retinoic acid receptor β (RAR β ) is frequently silenced in epithelial carcinogenesis, which has led to the hypothesis that RAR β acts as a tumor suppressor that is partially responsible for the limited clinical activity of classical retinoids ( 10 , 11 ) . Restoration of RAR β expression in premalignant oral lesions by isotretinoin treatment was associated with a benefi cial clinical response, implying a direct role for RAR β as a mediator of retinoid response and as a biomarker for clinical chemoprevention ( 12 ) . Clinical strategies to enhance retinoid activity include efforts to reduce toxicity, retain bioavailability, activate specifi c retinoid receptors, and develop effective combination regimens ( 1 ) . For example, topical alltrans -retinoic acid (tretinoin) has shown clinical activity in cervical intraepithelial neoplasia, overEDITORIALS