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The Retinoids and Cancer Prevention Mechanisms

^a The Norris Cotton Cancer Center and Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; ^b Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA

Correspondence: Konstantin H. Dragnev, M.D., Dartmouth Medical School, Department of Pharmacology and Toxicology, 7650 Remsen, Hanover, New Hampshire 03755, USA. Telephone: 603-650-1667; Fax: 603-650-1129; e-mail: Konstantin.H.Dragnev{at}dartmouth.edu

Carcinogenesis is a multistep process that converts normal cells into malignant cells. Once transformed, malignant cells acquire the ability to invade and metastasize, leading to clinically evident disease. During this continuum from normal to metastatic cells, carcinogenic steps can be arrested or reversed through pharmacological treatments, known as cancer chemoprevention. Chemoprevention strategies represent therapeutic interventions at early stages of carcinogenesis, before the onset of invasive cancer. Effective chemoprevention should reduce or avoid the clinical consequences of overt malignancies by treating early neoplastic lesions before development of clinically apparent signs or symptoms. Preclinical, clinical, and epidemiological data provide considerable support for cancer chemoprevention as an attractive therapeutic strategy. This clinical approach was validated in the recent tamoxifen randomized trial, demonstrating that a selective estrogen receptor modulator reduces the risk of breast cancer in women at high risk for this malignancy.

Derivatives of vitamin A, the retinoids, have reported activity in treating specific premalignant lesions and reducing incidence of second primary tumors in patients with prior head and neck, lung or liver cancers. Whether the retinoids will prevent primary cancers at these sites is not yet known. Notably, a carotenoid (ß-carotene) was shown as inactive in primary prevention of lung cancers in high-risk individuals. This underscores the need for relevant in vitro models to identify pathways signaling chemopreventive effects. These models should assess the activity of candidate chemoprevention agents before the conduct of large and costly prevention trials. An improved understanding of cancer prevention mechanisms should aid in the discovery of new therapeutic targets and chemoprevention agents. Ideally, these agents should have tolerable clinical toxicities suitable for chronic administration to individuals at high risk for developing primary or second cancers. This article reviews what is now known from clinical and preclinical studies about the retinoids as cancer prevention agents.

Key Words. Retinoids • Chemoprevention • Heterodimerization

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