The Retinoic Acid Paradox in Cancer Chemoprevention

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Decades of basic scientific 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 patients 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.