N-(4-Hydroxyphenyl)Retinamide in the Chemoprevention of Squamous Metaplasia and Dysplasia of the Bronchial Epithelium

• Published in: Clinical cancer research Vol. 6; no. 8; pp. 2973 - 2979
• Main Authors: Kurie, J M, Lee, J S, Khuri, F R, Mao, L, Morice, R C, Lee, J J, Walsh, G L, Broxson, A, Lippman, S M, Ro, J Y, Kemp, B L, Liu, D, Fritsche, H A, Xu, X, Lotan, R, Hong, W K
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-08-2000
• Subjects: Adult; Aged; Anticarcinogenic Agents - therapeutic use; Biopsy; Bronchi - drug effects; Bronchi - metabolism; Bronchi - pathology; Bronchoscopy; Epithelium - drug effects; Epithelium - metabolism; Epithelium - pathology; Female; Fenretinide - therapeutic use; Gene Expression - drug effects; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Male; Metaplasia - metabolism; Metaplasia - pathology; Metaplasia - prevention & control; Middle Aged; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Precancerous Conditions - prevention & control; Receptors, Retinoic Acid - biosynthesis; Receptors, Retinoic Acid - genetics; Signal Transduction - drug effects; Smoking - adverse effects
• ISSN: 1078-0432; 1557-3265

Lung cancer remains the number one cause of cancer-related deaths in the
United States. To reduce the mortality associated with this disease,
individuals at risk must be identified prior to the development of lung
cancer, and effective prevention strategies must be developed. One such
strategy is to use retinoids like
N -(4-hydroxyphenyl)retinamide (4-HPR), which has been
found to possess chemopreventive activities in preclinical studies. In
this study, 139 smokers were registered and 82 were randomized onto a
double-blinded, placebo-controlled chemoprevention trial of 4-HPR
administered p.o. (200 mg once daily). Of these, 70 participants were
eligible for response evaluation. Biopsies were obtained at six
predetermined sites in the bronchial tree from participants before and
at the completion of 6 months of treatment. 4-HPR treatment had no
measurable effect on histopathology (squamous metaplasia and dysplasia)
in the bronchial epithelium of current smokers. 4-HPR was detected
(104.5 ± 64.0 ng/ml, mean ± SD) in the serum of
participants, supporting its potential bioavailability. Serum retinol
levels decreased markedly (44% of placebo-treated patients) as a
consequence of 4-HPR treatment. Notably, the mRNA level of retinoic
acid receptor β, which is typically increased by retinoid treatment,
did not change in the bronchial epithelium of 4-HPR-treated
participants. Clonal populations of bronchial epithelial cells were
detected by analysis of loss of heterozygosity at putative tumor
suppressor loci on chromosomes 3p, 9p, and 17p, and these changes were
not altered by 4-HPR treatment. In conclusion, at this dose and
schedule, 4-HPR was not effective in reversing squamous metaplasia,
dysplasia, or genetic and phenotypic abnormalities in the bronchial
epithelium of smokers.