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.
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.
Kurie
Jonathan M
JM
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Lotan
Reuben
R
Lee
J Jack
JJ
Lee
Jin Soo
JS
Morice
Rodolfo C
RC
Liu
Diane D
DD
Xu
Xiao-Chun
XC
Khuri
Fadlo R
FR
Ro
Jae Y
JY
Hittelman
Walter N
WN
Walsh
Garrett L
GL
Roth
Jack A
JA
Minna
John D
JD
Hong
Waun Ki
WK
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*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D000077556:Alitretinoin; D014212:Tretinoin