Jm. Kurie et al., N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium, CLIN CANC R, 6(8), 2000, pp. 2973-2979
Lung cancer remains the number one cause of cancer-related deaths in the Un
ited States. To reduce the mortality associated with this disease, individu
als 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 f
ound to possess chemopreventive activities in preclinical studies. In this
study, 139 smokers were registered and 82 were randomized onto a double-bli
nded, placebo-controlled chemoprevention trial of 4-HPR administered p.o. (
200 mg once daily). Of these, 70 participants were eligible for response ev
aluation. Biopsies were obtained at six predetermined sites in the branchia
l tree from participants before and at the completion of 6 months of treatm
ent. 4-HPR treatment had no measurable effect on histopathology (squamous m
etaplasia 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 partic
ipants, supporting its potential bioavailability. Serum retinol levels decr
eased markedly (44% of placebo-treated patients) as a consequence of 4-HPR
treatment. Notably, the mRNA level of retinoic acid receptor beta, 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 put
ative tumor suppressor loci on chromosomes 3p, 9p, and 17p, and these chang
es were not altered by 4-HPR treatment. In conclusion, at this dose and sch
edule, 4-HPR was not effective in reversing squamous metaplasia, dysplasia,
or genetic and phenotypic abnormalities in the bronchial epithelium of smo
kers.