Kurie Jonathan M, Lotan Reuben, Lee J Jack, Lee Jin Soo, Morice Rodolfo C, Liu Diane D, Xu Xiao-Chun, Khuri Fadlo R, Ro Jae Y, Hittelman Walter N, Walsh Garrett L, Roth Jack A, Minna John D, Hong Waun Ki
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
J Natl Cancer Inst. 2003 Feb 5;95(3):206-14. doi: 10.1093/jnci/95.3.206.
Loss of retinoic acid receptor beta (RAR-beta) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus alpha-tocopherol (AT), could reverse RAR-beta expression loss in former smokers after 3 months of treatment.
Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-beta expression. McNemar's test was used to test changes in RAR-beta expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided.
A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-beta was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-beta expression (P =.03) and reduction of metaplasia (P =.01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-beta expression compared with placebo (P =.03).
9-cis-RA treatment can restore RAR-beta expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.
支气管上皮中视黄酸受体β（RAR-β）表达缺失被认为是肿瘤前病变的生物标志物。类视黄醇可以恢复该受体的表达，并可能阻止致癌作用的进展。本研究旨在调查两种基于类视黄醇的治疗方案，即9-顺式视黄酸（RA）或13-顺式视黄酸加α-生育酚（AT），在治疗3个月后是否能逆转既往吸烟者RAR-β表达缺失。
将吸烟至少20包年且已戒烟至少12个月的个体（n = 226）随机分配，分别接受为期3个月的每日口服9-顺式视黄酸（100 mg）、13-顺式视黄酸（1 mg/kg）+α-生育酚（1200 IU）或安慰剂治疗。在治疗前以及治疗后3个月和6个月，对支气管树的六个预定部位进行支气管镜检查和活检。对标本进行鳞状化生、发育异常和RAR-β表达评估。采用McNemar检验来检测各治疗组内RAR-β表达和鳞状化生的变化，并应用广义估计方程模型来模拟治疗效果，同时对协变量进行校正。所有统计检验均为双侧检验。
共有177名可评估受试者完成了至少3个月的治疗，并至少接受了基线和3个月时的支气管镜检查及活检评估。在所有基线活检样本中，69.7%检测到RAR-β，在240名受试者的所有基线样本中，6.9%有化生表现。在9-顺式视黄酸组中发现RAR-β表达恢复（P = 0.03）且化生减少（P = 0.01）。在对吸烟年数、每日吸烟包数和化生进行校正后，与安慰剂相比，9-顺式视黄酸治疗导致RAR-β表达有统计学意义的增加，而13-顺式视黄酸+α-生育酚治疗则无此效果（P = 0.03）。
9-顺式视黄酸治疗可恢复既往吸烟者支气管上皮中的RAR-β表达，这增加了这种类视黄醇在既往吸烟者中具有潜在化学预防特性的可能性。
