Placebo-controlled trial of 13-cis-retinoic acid activity on retinoic acid receptor-beta expression in a population at high risk: implications for chemoprevention of lung cancer.
OBJECTIVE
To establish the incidence of abnormalities in the expression of retinoic acid receptor-beta (RARbeta) in bronchial cells and determine the capacity of 13-cis-retinoic acid (13-CRA) to correct such abnormalities.


METHODS
One hundred eighty-eight smokers had a medical indication for bronchoscopy and were studied with bronchial brushings. Bronchial brushing samples were obtained for cytology analysis and for molecular analysis. After RNA was extracted, RARbeta sequences were amplified by reverse transcriptase polymerase chain reaction and Southern blots were performed to assess RARbeta expression. Forty-four eligible individuals with diminished RARbeta expression consented to double-blind randomization to receive a placebo or 13-CRA 30 mg orally daily for 6 months. A second bronchoscopy was performed at the end of the treatment period. An analysis of variance was used to analyze changes in RARbeta expression before and after treatment.


RESULTS
The 6-month treatment course was completed by 27 patients, and results were obtained for a total of 18 patients (eight patients treated with 13-CRA and ten treated with the placebo). In the placebo group, there was no difference between the results of RARbeta expression before and after treatment (P =.43). In the 13-CRA group, there was an upregulation of RARbeta expression at the end of 13-CRA treatment (P =.001). Cytologic changes were uncommon. Toxicities were primarily of grade 1. Palatal brushings were compared with bronchial brushings in 40 smokers. A perfect correlation of the results of RARbeta expression was obtained from 27 patients.


CONCLUSIONS
RARbeta expression is frequently decreased in the bronchial epithelium of smokers and is upregulated at the end of 13-CRA treatment. These results support undertaking a phase III chemoprevention trial of 13-CRA treatment for lung cancer.
Ayoub
J
J
Centre de recherche du Centre hospitalier de l'Université de Montréal and Hôpital Laval, Quebec, Canada. joseph.ayoub.chum@ssss.gouv.qc.ca
Jean-François
R
R
Cormier
Y
Y
Meyer
D
D
Ying
Y
Y
Major
P
P
Desjardins
C
C
Bradley
W E
WE
D000704:Analysis of Variance; D001980:Bronchi / Q000002:abnormalities / Q000166:cytology / Q000187:drug effects; D001999:Bronchoscopy; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D015474:Isotretinoin / Q000378:metabolism / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*; D015854:Up-Regulation
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D015474:Isotretinoin