CHEMOPREVENTION TRIAL IN FORMER SMOKERS

肺癌日益成为一种发生在过去的疾病 吸烟者。目前大约50%的肺癌发生在 吸烟者，随着戒烟者数量的持续增长(目前为44 在美国，这将成为一个日益严重的医疗保健问题。 必须制定策略来降低这一人群患肺癌的风险 通过识别高危个人和发展 有效的肺癌化学预防治疗。 这项提案将特别关注那些曾经吸烟者 可能治愈了先前的肺癌或喉癌。患有老年痴呆症的患者 既往与吸烟相关的癌症预计会有持续性支气管炎 化生和/或异型增生，这是肺癌的先兆，使 这些个体是整合生物标记物的理想人选 化学预防试验。336名符合条件的患者 将筛选符合资格的标准；其中80%(2681336)是 预计将同意接受支气管镜活检。约40% (106/268)这些患者预计符合资格标准 并参加这项双盲、安慰剂对照的试验，共13人- 顺式维甲酸(13cRA)联合α-生育酚。在这次审判中， 我们将解决以下具体目标： 具体目标1：证实癌前病变的持续性 通过测量其发病率和严重程度，对曾吸烟者的损害进行评估。 具体目标2：测定13cRA和α-生育酚对小鼠心脏功能的影响 逆转支气管化生和/或异型增生。 具体目标3：测量与~(13)cRA和α-受体相关的毒性 生育酚。 该提案将为项目2、3和4设定框架，该框架将 检查项目1的受试者13cRA和阿尔法的影响- 生育酚对肺癌发生的下列生物标志物的影响：诱变剂 敏感性和DNA修复能力(项目2)，遗传标记 不稳定和表型变化与放松生长和 分化(项目3)，以及维甲酸受体和维生素A 在支气管组织中的水平(项目4)。 我们先前的研究表明，13cRA可以逆转口腔癌前病变和 抑制有头颈部病史患者的第二原发癌 恶毒。因为对高剂量13cRA的研究一直受到 与治疗相关的毒性，这项试验还将包括α-生育酚， 它已被证明可以减轻13cRA相关的毒性。通过这些 努力，我们希望能洞察到支气管的潜力 化生和异型增生作为肺癌风险增加的标志 13cRA联合α-生育酚治疗肺癌的疗效观察 化学预防治疗。

Lung cancer is increasingly becoming a disease which occurs in former smokers. Approximately 50% of lung cancers currently happen in former smokers and, as the number of quitters continues to grow (currently 44 million in the U.S.), this will become an increasing health care problem. Strategies must be devised to reduce lung cancer risk in this population through the identification of high risk individuals and the development of effective lung cancer chemoprevention treatments. This proposal will specifically focus on former smokers who have been presumably cured of a prior lung or laryngeal cancer. Patients with a prior smoking-related cancer are expected to have persistent bronchial metaplasia and/or dysplasia, which are precursors for lung cancer, making these individuals ideal candidates for biomarker-integrated chemoprevention trials. Three hundred and thirty-six patients who meet the eligibility criteria will be screened; of these, 80% (2681336) are expected to agree to undergo bronchoscopic biopsies. Approximately 40% (106/268) of these patients are expected to meet the eligibility criteria and be enrolled on this double-blinded, placebo-controlled trial of 13- cis-retinoic acid (13cRA) combined with alpha-tocopherol. With this trial, we will address the following specific aims: Specific Aim 1: To confirm the persistence of premalignant bronchial lesions in former smokers by measuring its incidence and severity. Specific Aim 2: To determine the efficacy of 13cRA and alpha-tocopherol in reversing bronchial metaplasia and/or dysplasia. Specific Aim 3: To measure the toxicity associated with l3cRA and alpha- tocopherol. This proposal will set the framework for Projects 2, 3, and 4, which will examine the subjects of Project 1 for the effects of 13cRA and alpha- tocopherol on the following biomarkers of lung carcinogenesis: mutagen sensitivity and DNA repair capacity (Project 2), markers of genetic instability and phenotypic changes associated with deregulated growth and differentiation (Project 3), and retinoic acid receptors and vitamin A levels in bronchial tissues (Project 4). Our prior studies have shown that 13cRA can reverse oral premalignancy and inhibit second primary tumors in patients with a prior head and neck malignancy. Because studies with high-dose 13cRA have been limited by treatment-related toxicity, this trial will also include alpha-tocopherol, which has been shown to ameliorate 13cRA-related toxicity. Through these efforts, we hope to gain insight into the potential of bronchial metaplasia and dysplasia as markers of increased lung cancer risk and the usefulness of 13cRA combined with alpha-tocopherol as a lung cancer chemoprevention treatment.