LUNG CANCER CHEMOPREVENTION WITH BIOMARKER EVALUATION

本建议的主要目的是评估一个连续的 对发育不良支气管上皮的化学预防治疗方案， 将其对组织病理学的影响与几种生物标志物相关联。我们计划 招募225名重度吸烟者（大于30包-年）， 在两年的时间里有明显的肺癌证据。新开发的 荧光支气管镜检查法检测支气管发育不良 其灵敏度比传统的高两倍以上， 白光支气管镜检查将用于定位潜在的异型增生 支气管病变行活检病理证实。八十 活检证实支气管发育不良的受试者将入组 视黄醇（Aquasol A）50，000 IU/天与 安慰剂6个月。病变的组织病理学分级变化， 病变基础将用作干预的主要终点。 这将通过荧光支气管镜检查和精确的再活检来实现 在基线时发现发育不良的所有区域以及任何新的 研究药物治疗6个月结束时出现的病变。科目 发育不良逆转的患者将在一年后进行第三次支气管镜检查 药物治疗，以确定长期结果。那些有稳定的，新的 或进行性病变后6个月的维甲酸/安慰剂将进入 a茴三醇（Sialor）的II期毒性和可行性试验 25 mg po tid，6个月。将在以下时间进行重复支气管活检： 6个月后评估结果。其他的用处 支气管活组织检查中的生物标志物如类维生素A酸受体（RAR-p）， 在3 p、5 q、9 p、p53或Rb中的洛缺失，端粒酶表达和定量 形态测定（包括DNA含量和核纹理特征） 将作为结局的潜在中间终点进行检查 可能无法完全反映在 光是组织病理学 探讨采用一种非侵入性的方法来识别，在高危 群体，个人窝藏癌前肺病变（S），三个DAB 将从所有225例受试者中采集合并痰液细胞学标本 在基线支气管镜检查之前。进展的存在 （二）相关变更（PAC）将使用 自动定量图像细胞仪。结果将相互关联 在支气管镜检查中存在/不存在支气管发育不良， 确定PAC是否可用于风险评估。此外， 将每月在参加研究的受试者亚组中采集标本 药物，以确定PAC是否可用于监测对 化学预防疗法 这项研究将提供新的信息，使用新的生物标志物， 识别具有癌前支气管病变的个体， 使用这些生物标志物作为中间终点， 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.