Treatment of Former Smokers With 9-cis-Retinoic Acid Reverses Loss of Retinoic Acid Receptor-β Expression in the Bronchial Epithelium: Results From a Randomized Placebo-Controlled Trial

• Published in: JNCI : Journal of the National Cancer Institute 2003-02, Vol.95 (3), p.206-214
• Main Authors: Kurie, Jonathan M., Lotan, Reuben, Lee, J. Jack, Lee, Jin Soo, Morice, Rodolfo C., Liu, Diane D., Xu, Xiao-Chun, Khuri, Fadlo R., Ro, Jae Y., Hittelman, Walter N., Walsh, Garrett L., Roth, Jack A., Minna, John D., Hong, Waun Ki
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alitretinoin; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biopsy; Bronchi - drug effects; Bronchi - metabolism; Bronchi - pathology; Bronchoscopy; Chemotherapy; Double-Blind Method; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; In Situ Hybridization; Male; Medical sciences; Metaplasia - metabolism; Metaplasia - prevention & control; Middle Aged; Pharmacology. Drug treatments; Precancerous Conditions - metabolism; Precancerous Conditions - prevention & control; Receptors, Retinoic Acid - drug effects; Receptors, Retinoic Acid - metabolism; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; RNA, Messenger - analysis; Smoking - adverse effects; Smoking - metabolism; Tretinoin - adverse effects; Tretinoin - therapeutic use
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/95.3.206

Background: Loss of retinoic acid receptor beta (RAR-β) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus α-tocopherol (AT), could reverse RAR-β expression loss in former smokers after 3 months of treatment. Methods: Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-β expression. McNemar’s test was used to test changes in RAR-β expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided. Results: A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-β was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-β expression (P = .03) and reduction of metaplasia (P = .01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-β expression compared with placebo (P = .03). Conclusion: 9-cis-RA treatment can restore RAR-β expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.