Proliferative changes in the bronchial epithelium of former smokers treated with retinoids.
BACKGROUND
Retinoids have shown antiproliferative and chemopreventive activity. We analyzed data from a randomized, placebo-controlled chemoprevention trial to determine whether a 3-month treatment with either 9-cis-retinoic acid (RA) or 13-cis-RA and alpha-tocopherol reduced Ki-67, a proliferation biomarker, in the bronchial epithelium.


METHODS
Former smokers (n = 225) were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) and alpha-tocopherol (1200 IU), or placebo. Bronchoscopic biopsy specimens obtained before and after treatment were immunohistochemically assessed for changes in the Ki-67 proliferative index (i.e., percentage of cells with Ki-67-positive nuclear staining) in the basal and parabasal layers of the bronchial epithelium. Per-subject and per-biopsy site analyses were conducted. Multicovariable analyses, including a mixed-effects model and a generalized estimating equations model, were used to investigate the treatment effect (Ki-67 labeling index and percentage of bronchial epithelial biopsy sites with a Ki-67 index > or = 5%) with adjustment for multiple covariates, such as smoking history and metaplasia. Coefficient estimates and 95% confidence intervals (CIs) were obtained from the models. All statistical tests were two-sided.


RESULTS
In per-subject analyses, Ki-67 labeling in the basal layer was not changed by any treatment; the percentage of subjects with a high Ki-67 labeling in the parabasal layer dropped statistically significantly after treatment with 13-cis-RA and alpha-tocopherol treatment (P = .04) compared with placebo, but the drop was not statistically significant after 9-cis-RA treatment (P = .17). A similar effect was observed in the parabasal layer in a per-site analysis; the percentage of sites with high Ki-67 labeling dropped statistically significantly after 9-cis-RA treatment (coefficient estimate = -0.72, 95% CI = -1.24 to -0.20; P = .007) compared with placebo, and after 13-cis-RA and alpha-tocopherol treatment (coefficient estimate = -0.66, 95% CI = -1.15 to -0.17; P = .008).


CONCLUSIONS
In per-subject analyses, treatment with 13-cis-RA and alpha-tocopherol, compared with placebo, was statistically significantly associated with reduced bronchial epithelial cell proliferation; treatment with 9-cis-RA was not. In per-site analyses, statistically significant associations were obtained with both treatments.
Hittelman
Walter N
WN
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Box 19, 1515 Holcombe Blvd, Houston, TX 77030, USA. whittelm@mdanderson.org
Liu
Diane D
DD
Kurie
Jonathan M
JM
Lotan
Reuben
R
Lee
Jin Soo
JS
Khuri
Fadlo
F
Ibarguen
Heladio
H
Morice
Rodolfo C
RC
Walsh
Garrett
G
Roth
Jack A
JA
Minna
John
J
Ro
Jae Y
JY
Broxson
Anita
A
Hong
Waun Ki
WK
Lee
J Jack
JJ
D000328:Adult; D000368:Aged; D000077556:Alitretinoin; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015474:Isotretinoin / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012107:Research Design; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology; D012907:Smoking; D016540:Smoking Cessation; D014212:Tretinoin / Q000627:therapeutic use*; D024502:alpha-Tocopherol / Q000627:therapeutic use*
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D015415:Biomarkers; D019394:Ki-67 Antigen; D000077556:Alitretinoin; D014212:Tretinoin; D015474:Isotretinoin; D024502:alpha-Tocopherol