Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: results from a randomized placebo-controlled trial

J Natl Cancer Inst. 2003 Feb 5;95(3):206-14. doi: 10.1093/jnci/95.3.206.


Background: Loss of retinoic acid receptor beta (RAR-beta) 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 alpha-tocopherol (AT), could reverse RAR-beta 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-beta expression. McNemar's test was used to test changes in RAR-beta 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-beta 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-beta 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-beta expression compared with placebo (P =.03).

Conclusion: 9-cis-RA treatment can restore RAR-beta expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alitretinoin
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biopsy
  • Bronchi* / drug effects
  • Bronchi* / metabolism
  • Bronchi* / pathology
  • Bronchoscopy
  • Double-Blind Method
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • In Situ Hybridization
  • Male
  • Metaplasia / metabolism
  • Metaplasia / prevention & control
  • Middle Aged
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / prevention & control*
  • RNA, Messenger / analysis
  • Receptors, Retinoic Acid / drug effects*
  • Receptors, Retinoic Acid / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology*
  • Smoking / adverse effects
  • Smoking / metabolism*
  • Tretinoin / adverse effects
  • Tretinoin / therapeutic use*


  • Antineoplastic Agents
  • RNA, Messenger
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Alitretinoin
  • Tretinoin