Lam Stephen, Xu Xiaochun, Parker-Klein Helga, Le Riche Jean C, Macaulay Calum, Guillaud Martial, Coldman Andy, Gazdar Adi, Lotan Reuben
Department of Respiratory Therapy, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 3J5, Canada.
Int J Oncol. 2003 Dec;23(6):1607-13.
Epidemiological studies suggested that vitamin A may be protective against lung cancer, however, recent chemoprevention trials with beta-carotene, a precursor of vitamin A, demonstrated enhancement of lung carcinogenesis among smokers. Whether vitamin A is beneficial or harmful in chemoprevention of lung cancer in smokers has not been resolved. This study was designed to determine the effect of retinol alone in current and former smokers using bronchial dysplasia, nuclear morphometry and retinoic acid receptor-beta (RAR-beta) mRNA expression as surrogate end-point biomarkers (SEBs). Eighty-one current or former smokers with a smoking history of >/=30 pack-years were randomized to receive either placebo or retinol (50,000 IU per day) for six months. Fluorescence bronchoscopy was performed prior to treatment to localize areas suggestive of dysplasia. At least 4 bronchial biopsies were taken per subject including at least two biopsies from apparently normal areas. The same areas were precisely re-biopsied after 6 months. Any new areas suggestive of dysplasia were also biopsied. Changes in the SEBs were assessed before and after treatment. At baseline, the frequency of biopsies negative for RAR-beta expression was: normal (23%), hyperplasia (28%), metaplasia (41%), mild dysplasia (41%), and moderate/severe dysplasia (44%). There was no significant difference in the regression rate between the retinol and placebo groups using histopathology and nuclear morphometry as SEBs. The likelihood of regression was found to be lower in those who continued to smoke during the study (OR=1.86 for those smoking >10 cigarettes per day, p=0.084 to OR=0.95, p=0.26 for those smoking 20+ per day compared to ex-smokers). Retinol was not effective in the up-regulation of RAR-beta in lesions with bronchial dysplasia. We postulate that the lack of effect of retinol on RAR-beta expression among individuals who continued to smoke while taking retinol may be due to suppressive effect of tobacco smoke constituents on RAR-beta expression and/or altered cellular metabolism of retinol to retinoic acid and its isomers.
流行病学研究表明维生素A可能对肺癌有预防作用，然而，最近以维生素A的前体β-胡萝卜素进行的化学预防试验显示，吸烟者的肺癌发生风险增加。维生素A在吸烟者肺癌化学预防中是有益还是有害尚未明确。本研究旨在以支气管发育异常、核形态计量学和维甲酸受体-β（RAR-β）mRNA表达作为替代终点生物标志物（SEB），确定单独使用视黄醇对现吸烟者和既往吸烟者的影响。81名吸烟史≥30包年的现吸烟者或既往吸烟者被随机分为两组，分别接受安慰剂或视黄醇（每日50,000 IU）治疗6个月。治疗前进行荧光支气管镜检查以定位提示发育异常的区域。每位受试者至少取4份支气管活检标本，包括至少两份取自外观正常区域的标本。6个月后对相同区域进行精确再次活检。任何新出现的提示发育异常的区域也进行活检。在治疗前后评估SEB的变化。基线时，RAR-β表达阴性的活检标本频率为：正常（23%）、增生（28%）、化生（41%）、轻度发育异常（41%）和中度/重度发育异常（44%）。以组织病理学和核形态计量学作为SEB，视黄醇组和安慰剂组的消退率无显著差异。研究发现，在研究期间继续吸烟的人群中，消退的可能性较低（与戒烟者相比，每日吸烟>10支者的OR = 1.86，p = 0.084；每日吸烟≥20支者的OR = 0.95，p = 0.26）。视黄醇对支气管发育异常病变中RAR-β的上调无效。我们推测，在服用视黄醇期间继续吸烟的个体中，视黄醇对RAR-β表达缺乏作用，可能是由于烟草烟雾成分对RAR-β表达的抑制作用和/或视黄醇向维甲酸及其异构体的细胞代谢改变所致。
