N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium

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.