title: 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.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Rodolfo C
authors.initials: RC
authors.lastname: Morice
authors.forename: Diane D
authors.initials: DD
authors.lastname: Liu
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Xu
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Jae Y
authors.initials: JY
authors.lastname: Ro
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Garrett L
authors.initials: GL
authors.lastname: Walsh
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001706:Biopsy; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001999:Bronchoscopy; D004311:Double-Blind Method; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008679:Metaplasia / Q000378:metabolism / Q000517:prevention & control; D008875:Middle Aged; D011230:Precancerous Conditions / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D000077556:Alitretinoin; D014212:Tretinoin