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

摘要 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年的戒烟计划和反吸烟运动减少了 在美国，吸烟的流行率增加了三分之二。目前，以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，曾经吸烟的人患肺癌的风险仍然很高 好几年了。大多数新的肺癌病例发生在前吸烟者中。不幸的是，预防性干预对 曾经的吸烟者中仍然缺乏肺癌的病例。这项拟议的主体证明研究旨在评估 葡萄糖胺天然产物萝卜硫素的化学预防作用 十字花科蔬菜对降低肺癌发病机制的细胞和分子危险生物标志物的作用。 从十字花科蔬菜中提取的萝卜硫醚和其他异硫氰酸酯显示出很好的前景。 临床前动物实验、流行病学研究和短期研究中的化学预防特性 人体随机临床试验。饮食中摄入萝卜硫素可显著降低糖尿病的发病率。 烟草致癌物诱发肺腺癌的动物模型模拟以前的情景 吸烟者，伴随着细胞增殖标记物Ki-67的降低和细胞凋亡的增加 标记物caspase-3和TUNEL。在人体短期临床试验中，萝卜硫素的摄入增加了 环境致癌物解毒，Ki-67指数降低。流行病学研究表明， 大量摄入十字花科蔬菜或异硫氰酸酯与降低患肺癌的风险显著相关。 人类的癌症。然而，临床试验表明萝卜硫素具有较长期的治疗作用。 目前缺乏肺癌发病机制的生物标志物。 这项拟议的随机、双盲、安慰剂对照的2期临床试验将纳入72名前 吸烟者患肺癌的风险很高。所有受试者将被随机分配到任一治疗(每日最低限度 12个月的萝卜硫素剂量)或安慰剂。支气管镜引导下的支气管镜活检和 刷牙，支气管肺泡灌洗，鼻部刷牙，血液和尿液样本将在治疗前后采集。 干预。其具体目的是(1)确定硫烷是否调节支气管的变化 支气管异型增生指数、细胞增殖标记物Ki-67、细胞凋亡标记物caspase-3和TUNEL 活检，所有这些都被证明与肺癌的发病机制直接相关；以及(2)确定 如果萝卜硫素调节支气管和鼻黏膜上皮基因表达标记物的变化， 已被证明与肺癌的发生有直接联系。拟议研究的结果 将在减少肺癌发病率和死亡率方面对公共卫生产生重大影响 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 可获得的，廉价的，天然的化合物，作为主要的化学预防药物。

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.