LUNG CANCER CHEMOPREVENTION WITH BIOMARKER EVALUATION

该提案的主要目的是评估一系列 支气管上皮发育不良的化学预防治疗方案 将其在组织病理学中的作用与几个生物标志物联系起来。我们计划 招募225名重度吸烟者(超过30包年) 两年内有明显肺癌的证据。一种新开发的 一种可发现支气管异型增生的荧光支气管镜检查方法 敏感度比传统的两倍还多 白光支气管镜检查将用于定位潜在的发育不良 支气管镜下活检病理证实。八十 活检证实为支气管发育不良的受试者将参加一项 视黄醇(Aquasol A)50IU/d与维甲酸(Aquasol A)50IU/d的随机临床试验 安慰剂6个月。病变的组织病理学分级的变化 病变基础将被用作介入的主要终点。 这将通过荧光支气管镜检查和精确的再活检来实现。 所有在基线上发现有异型增生的区域以及任何新的 研究用药6个月结束时出现皮损。科目 随着异型增生的逆转，第三次支气管镜检查将推迟一年 决定长期结果的药物治疗。那些拥有稳定的，新的 或进行性皮损在服用维甲酸/安慰剂6个月后进入 茴香三硫酮(SIALOR)的II期毒性及可行性试验 25 mg，po，tid，疗程6个月。重复的支气管镜检查将在 在6个月结束时评估结果。其他的有用之处 支气管活检中的生物标记物，如维甲酸受体(RAR-p)， 3p、5q、9p、P53或Rb基因缺失、端粒酶表达及定量 形态计量学(包括DNA含量和核纹理特征) 将作为潜在的中间终点(S)进行检查以确定结果 评估可能不会完全反映在 仅仅是组织病理学。 探索使用非侵入性方法识别高危人群 肺肿瘤前病变的群体、个人(S)，三联 将从所有225名受试者中获得汇集的痰细胞学样本 在基线支气管镜检查之前。级数的存在 (恶性)相关改变(PAC)将使用 自动定量图像细胞仪。结果将会相互关联 支气管镜检查有/无支气管异型增生 确定PAC是否可用于风险评估。此外，痰 每月将在研究对象子集中获取样本 用药来确定PAC是否可以用于监测对 化学预防疗法。 这项研究将为新的生物标志物的使用提供新的信息。 识别患有癌前支气管炎病变的个体 使用这些生物标志物作为中间终点来评估 化学预防的效果。

The main purpose of this proposal is to evaluate a sequential chemopreventive therapy regimen on dysplastic bronchial epithelium and correlate its effect on histopathology and several biomarkers. We plan to recruit 225 heavy smokers (greater than 30 pack-years) without evidence of overt lung cancer over a two year period. A newly developed fluorescence bronchoscopic method that can detect bronchial dysplasia with a sensitivity that is more than twofold better than conventional white-light bronchoscopy will be used to localize potential dysplastic bronchial lesions for biopsy for pathological confirmation. Eighty subjects with biopsy proven bronchial dysplasia will be enrolled into a randomized clinical trial of retinol (Aquasol A) 50,000 IU/day versus placebo for 6 months. Changes in histopathology grade on a lesion by lesion basis will be used as the primary end-point for the intervention. This will be achieved by fluorescence bronchoscopy and precise re-biopsy of all areas found to have dysplasia at baseline as well as any new lesions appearing at the end of 6 months of study medication. Subjects with reversion of dysplasia will have a third bronchoscopy one year off medication to determine the long term outcome. Those who have stable, new or progressive lesions after 6 months of retino/placebo will enter into a Phase II toxicity and feasibility trial of anetholatrithione (Sialor) 25 mg po tid for 6 months. Repeat bronchial biopsy will be performed at the end of 6 months to assess the outcome. The usefulness of other biomarkers in bronchial biopsies such as retinoid acid receptor (RAR-p), LOH in 3p, 5q, 9p, p53, or rb, telomerase expression and quantitative morphometry (which includes DNA content and nuclear textural features) will be examined as potential intermediate end-point(s) for outcome assessment which may not be completely reflected by changes in histopathology alone. To explore the use of a non-invasive method to identify, in high risk groups, individuals harboring pre-neoplastic lung lesion(s), a three-dab pooled sputum cytology specimen will be obtained from all 225 subjects prior to the baseline bronchoscopy. The presence of Progression (Malignancy) Associated Changes (PACs) will be examined using an automated quantitative image cytometer. The results will be correlated with the presence/absence of bronchial dysplasia on bronchoscopy to determine if PACs can be used for risk assessment. In addition, sputum specimens will be obtained monthly in the subset of subjects taking study medication to determine if PACs can be used to monitor the response to chemopreventive therapy. The study will provide new information on the use of novel biomarkers for identifying individuals harboring preneoplastic bronchial lesions and on the use of these biomarkers as intermediate end-points for assessing the effect of chemoprevention.