Retinol, Vitamins, and Cancer Prevention: 25 Years of Learning and Relearning
Authors: Gary E. Goodman, David S. Alberts, Frank L. Meyskens
Journal: Journal of Clinical Oncology (2008)

VOLUME NUMBER DECEMBER J OURNAL OF C LINICAL O NCOLOGY CELEBRATING 25 YEARS OF JCO Retinol, Vitamins, and Cancer Prevention: 25 Years of Learning and Relearning Gary E. Goodman, Swedish Cancer Institute and Fred Hutchinson Cancer Research Center, Seattle, WA David S. Alberts, University of Arizona, Tucson, AZ Frank L. Meyskens, University of California, Irvine, Irvine, CA Twenty-five years ago, we published a phase I trial of retinol in cancer patients. 1 By today’s standards, this phase I trial left much to be desired. The sample size of 13 patients, the methods to evaluate ad- verse effects (remember radionuclide liver-spleen scans?), and the lack of pharmacokinetics are just a few areas that make it seem naive. However, although deficient by today’s standards, the unique aspects of that trial remain—the potential target population and the agent being studied, retinol (ie, vitamin A). In 1983, the retinoids, vitamin A and its family of naturally occurring and synthetic analogs, were just entering the realm of clinical investigation. In 1979, Sporn and Newton 2 published their landmark article on the retinoids and introduced the concept of che- moprevention—the possibility that we could prevent, arrest, or re- verse carcinogenesis by the administration of exogenous agents. At the time, simple in vivo and in vitro experiments suggested that retinoids could act as chemoprevention agents. In addition, trans- and cis- retinoic acid had shown some activity in patients with established cancers. 3,4 The group at the University of Arizona Cancer Center led by Dr Frank Meyskens initiated studies to investigate the potential of the retinoids for treating cancer and as cancer prevention agents. The 1983 phase I trial was one of a series of trials testing retinol, retinyl palmitate, and 13-cis-retinoic acid. These phase I and II trials were among the first studying potential chemoprevention agents and set a precedent for their clinical evaluation. Another important aspect of this trial was the recognition of dietary micronutrients and vitamins as biologically active agents that deserved laboratory and clinical investigation. In the late 1970s and early 1980s, the study of vitamins in cancer prevention and treatment was more in the realm of alternative treatment. A re-evaluation was supported by the increase in nutritional epidemiology and the find- ings of inverse associations between the intake of foods rich in certain vitamins and cancer incidence. Over time, epidemiologic studies became more sophisticated in analyzing dietary constituents and included serum concentrations of micronutrients. The inverse associations with specific cancers held. Although plagued with poten- tial confounders, these studies suggested that low serum concentra- tions of retinol and its precursor ( ␤ -carotene) were risk factors for many cancers. 5,6 In parallel, work by Lotan and Clifford 7 and others describing additional synthetic retinoids, retinoid receptors, and their role in cancer and normal cellular differentiation gave the area a strong basic science foundation. It was clear that the retinoids had an impor- tant biologic role (they are vital amines are they not?) and that their manipulation may result in clinical benefit. In 1983, literature describing the clinical use of the retinoids was scant. None of the newer retinoids were available for clinical use, and toxicity reports were anecdotal and consisted almost exclusively of accidental or health enthusiast overdosing with retinol or retinyl palmitate. Because these agents had a potential for use in cancer treatment as well as cancer prevention, we decided that they should be treated like any biologically active drug. Their potential for use in a healthy but high-risk population made it imperative to have a clear understanding of the dose-toxicity relationship. Hence, we studied the retinoids as we would any phase I cancer agent. Our phase I trial of retinol was closely followed by a phase II trial in cancer patients 8 and later used in a large phase III chemoprevention trial (Carotene and Retinol Efficacy Trial [CARET]). 9 Since those early days, many years have passed, and we have learned much. In the area of therapeutics, retinoids are now approved for clinical use and are part of standard treatment protocols—trans- retinoic acid for acute promyelocytic leukemia, 13-cis-retinoic acid for acne, and bexarotene for cutaneous T-cell lymphoma. In the area of chemoprevention, retinoids and their dietary pre- cursor ( ␤ -carotene) were some of the first agents to be tested in large population-based trials. In the National Cancer Institute-sponsored trials in Linxian, China, both ␤ -carotene and retinol were part of the nutritional combinations tested. In this nutritionally deficient popu- lation, the combination of ␤ -carotene, ␣ -tocopherol, and selenium showed a decrease in cancer incidence and a survival advantage. 10 The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial in Finland and our CARET trial in the United States studied ␤ -carotene along with ␣ -tocopherol (ATBC) and retinol (CARET) in cigarette smokers. 11 These studies in a nutritionally adequate population did not show benefit from either retinol or ␤ -carotene supplementation; both ATBC and CARET found a significant increase in lung cancer incidence in the retinol/ ␤ -carotene– containing arms within 1 to 2 years of administration. That first generation of chemoprevention trials taught us much. Our enthusiasm of intervening with harmless micronutrients or vita- mins has been tempered by a better understanding of the complexity of carcinogenesis and the complexity, but still poor understanding, of the mechanism and scope of biologic activity of vitamins and micro- nutrients. The findings of increased lung cancer incidence in both the Journal of Clinical Oncology, Vol 26, No 34 (December 1), 2008: pp 5495-5496 DOI: 10.1200/JCO.2008.19.0884; published online ahead of print at www.jco.org on November 3, 2008 © 2008 by American Society of Clinical Oncology