Randomized Clinical Trial of Lung Cancer Chemoprevention with Sulforaphane in Former Smokers

前吸烟者用萝卜硫素化学预防肺癌的随机临床试验

• 批准号: 9380009
• 负责人: Jian-Min Yuan
• 金额: $ 63.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-14 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380009
• 关键词: Animal Experiments; Animal Model; Antismoking; Apoptosis; Benign; Biological; Biological Markers; Biopsy; Blood; Breast; Broccoli - dietary; Bronchoalveolar Lavage; Bronchoscopy; CASP3 gene; Cancer Etiology; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical Trials; DNA Methylation; Dace; Dietary Isothiocyanate; Dietary intake; Dose; Double-Blind Method; Drug Metabolic Detoxication; Dysplasia; Early Diagnosis; Enrollment; Environmental Carcinogens; Experimental Animal Model; Future; Gene Expression; Genes; Goals; Histologic; Human; In Situ Nick-End Labeling; Incidence; Induction of Apoptosis; Inhibition of Cell Proliferation; Injury; Intake; Intervention Trial; Isothiocyanates; Lesion; Link; Lung Adenocarcinoma; Malignant neoplasm of lung; Molecular; Molecular Profiling; Nasal Epithelium; Natural Products; Nose; Participant; Pathogenesis; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Placebos; Pre-Clinical Model; Premalignant; Premalignant Change; Prevalence; Prevention strategy; Preventive Intervention; Primary Prevention; Proliferation Marker; Property; Public Health; Randomized; Randomized Clinical Trials; Recruitment Activity; Reporting; Research; Risk; Risk Reduction; Rodent Model; Role; Sampling; Smoker; Sulforaphane; Tissues; Tobacco-Associated Carcinogen; Toxic Environmental Substances; Urine; Vegetables; Woman; base; bronchial epithelium; cancer chemoprevention; cancer diagnosis; cancer prevention; cancer risk; cigarette smoking; cruciferous vegetable; epidemiologic data; epidemiology study; experimental study; glucoraphanin; high risk; high risk population; indexing; lung cancer prevention; lung cancer screening; lung carcinogenesis; lung development; member; molecular marker; mortality; multidisciplinary; nutrition; post intervention; pre-clinical; programs; smoking cessation

ABSTRACT Lung cancer is the leading cause of cancer death. Cigarette smoking is the most important causal factor. The smoking cessation program and antismoking campaign over the past 50 years has reduced the prevalence of cigarette smoking by two-thirds in the US. Currently there are more former smokers than current smokers. However, former smokers remain at high risk of lung cancer even after quitting smoking for many years. Majority new lung cancer cases occur among former smokers. Unfortunately preventive intervention for lung cancer among former smokers is still lacking. This proposed proof-of-principal study is to evaluate the chemopreventive potentials of sulforaphane, a natural product formed from glucoraphanin in certain cruciferous vegetables, on reducing the cellular and molecular risk biomarkers of lung cancer pathogenesis. Sulforaphane and other isothiocyanates derived from cruciferous vegetables have shown promising chemopreventive properties in preclinical animal experiments, and in epidemiological studies and short-term randomized clinical trials in humans. Dietary intake of sulforaphane significantly reduced the incidence of tobacco-carcinogen induced lung adenocarcinoma in animal models that mimicked the scenario as former smokers, along with the concurrent reduction of cell proliferation marker Ki-67 and the increase of apoptosis markers caspase-3 and TUNEL. In short-term clinical trials in humans, intake of sulforaphane enhanced the detoxification of environmental carcinogens and reduced Ki-67 index. Epidemiological studies demonstrated that high intake of cruciferous vegetables or isothiocyanates was associated signficantly with reduced risk of lung cancer in humans. However, clinical trials with a relatively long-term treatment of sulforaphane on the modulation of lung cancer pathogenesis biomarkers are lacking. This proposed randomized, double-blinded, placebo-controlled, phase 2 clinical trial will enroll 72 former smokers at high risk for lung cancer. All subjects will be randomly assigned to either treatment (daily minimal dose of 120 µmol sulforaphane for 12 months) or placebo. Bronchoscopy-guided bronchial biopsy and brushing, bronchoalveolar lavage, and nasal brushing, blood and urine samples will be collected pre- and post- intervention. The specific aims are (1) to determine if sulforphane modulates the changes of bronchial dysplasia index, cell proliferation marker Ki-67, and apoptosis markers caspase-3 and TUNEL in bronchial biopsies, all of which have shown to be directly associated with lung cancer pathogenesis; and (2) to determine if sulforaphane modulate the changes of the gene expression markers in bronchial and nasal epithelia that have been shown to be directly linked to the development of lung cancer. The findings of the proposed study will have significant public health implication in reducing lung cancer incidence and mortality in former smokers. The ultimate goal is to develop, evaluate, and validate the efficacy of this readily available, widely accessible, inexpensive, natural compound as a primary chemopreventive agent.

抽象的 肺癌是癌症死亡的主要原因。吸烟是最重要的原因 因素。过去 50 年来的戒烟计划和反吸烟运动减少了 美国三分之二的人吸烟。目前，前吸烟者比现在吸烟者多 吸烟者。然而，即使在许多人戒烟后，前吸烟者仍然面临着较高的肺癌风险。 年。大多数新的肺癌病例发生在以前吸烟的人中。不幸的是，预防性干预 戒烟者中肺癌的发病率仍然很低。这项拟议的原理证明研究旨在评估 萝卜硫素的化学预防潜力，萝卜硫素是一种由萝卜硫素在某些情况下形成的天然产物 十字花科蔬菜，可降低肺癌发病机制的细胞和分子风险生物标志物。 从十字花科蔬菜中提取的萝卜硫素和其他异硫氰酸盐已显示出良好的应用前景 临床前动物实验、流行病学研究和短期化学预防特性 人体随机临床试验。膳食中摄入萝卜硫素可显着降低以下疾病的发生率 烟草致癌物在动物模型中诱发肺腺癌，模拟了以前的情况 吸烟者，细胞增殖标志物 Ki-67 同时减少，细胞凋亡增加 标记 caspase-3 和 TUNEL。在人体短期临床试验中，摄入萝卜硫素可增强 解毒环境致癌物并降低Ki-67指数。流行病学研究表明 大量摄入十字花科蔬菜或异硫氰酸盐与降低患肺癌的风险显着相关 人类癌症。然而，相对长期治疗萝卜硫素对调节的临床试验 肺癌发病机制生物标志物缺乏。 这项拟议的随机、双盲、安慰剂对照 2 期临床试验将招募 72 名前 吸烟者是肺癌的高危人群。所有受试者将被随机分配至任一治疗组（每日最少 剂量为 120 µmol 萝卜硫素，持续 12 个月）或安慰剂。支气管镜引导下的支气管活检和 刷牙、支气管肺泡灌洗和鼻刷，将在治疗前和治疗后收集血液和尿液样本 干涉。具体目标是（1）确定磺基是否调节支气管的变化 支气管发育不良指数、细胞增殖标志物Ki-67、凋亡标志物caspase-3、TUNEL 活检，所有这些都已被证明与肺癌发病机制直接相关； (2) 确定 如果萝卜硫素调节支气管和鼻上皮基因表达标记的变化 已被证明与肺癌的发生直接相关。拟议研究的结果 将对降低以前的肺癌发病率和死亡率产生重大的公共卫生影响 吸烟者。最终目标是开发、评估和验证这种现成的、广泛使用的药物的功效 容易获得、廉价的天然化合物作为主要化学预防剂。