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 因子过去50年的戒烟计划和反吸烟运动减少了 吸烟率下降了三分之二。目前，吸烟者比吸烟者多。 吸烟者。然而，即使在许多人戒烟后，前吸烟者仍然处于肺癌的高风险之中。 年大多数新的肺癌病例发生在以前的吸烟者中。不幸的是， 戒烟者患肺癌的情况仍然缺乏。这项拟议的主要研究证明是为了评估 萝卜硫素的化学预防潜力，萝卜硫素是一种天然产物， 十字花科蔬菜，降低肺癌发病机制的细胞和分子风险生物标志物。 萝卜硫素和其他异硫氰酸酯来自十字花科蔬菜已显示出有前途的 在临床前动物实验，流行病学研究和短期的化学预防特性 人体随机临床试验。膳食摄入萝卜硫素显著降低了 烟草致癌物诱导的肺腺癌的动物模型，模仿的情况下， 吸烟者，沿着细胞增殖标志物Ki-67的同时减少和细胞凋亡的增加 标记caspase-3和TUNEL。在人类的短期临床试验中，摄入萝卜硫素可以增强 解毒环境致癌物和降低Ki-67指数。流行病学研究表明， 高摄入量的十字花科蔬菜或异硫氰酸酯与降低肺部疾病的风险显著相关。 人类的癌症然而，具有萝卜硫素调节的相对长期治疗的临床试验， 缺乏肺癌发病机制生物标志物。 这项拟议的随机、双盲、安慰剂对照的2期临床试验将招募72名前 吸烟者患肺癌的风险高。所有受试者将被随机分配至任一治疗组（每日最低 120 μmol莱菔硫烷12个月）或安慰剂。支气管镜引导下支气管活检， 刷牙、支气管肺泡灌洗和鼻腔刷牙，将在刷牙前后采集血液和尿液样本， 干预本研究的目的是：（1）确定硫啡烷是否调节支气管平滑肌的变化， 支气管粘膜异型增生指数、细胞增殖标记物Ki-67、凋亡标记物caspase-3和TUNEL 活组织检查，所有这些都显示与肺癌发病机制直接相关;以及（2）确定 如果萝卜硫素调节支气管和鼻上皮中基因表达标志物的变化， 已被证明与肺癌的发展直接相关。拟议研究的结果 将对减少前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、广泛的 可获得的，廉价的，天然化合物作为主要的化学预防剂。

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.