Chemoprevention of Lung Cancer

肺癌是美国男性和女性的主要死因(2001年新增病例16万例，死亡157400例)。尽管戒烟的吸烟者患肺癌的相对风险有所下降，但戒烟者在至少5年内仍处于高风险状态。由于戒烟是一项重大的公共卫生倡议，以前吸烟者在肺癌中所占的比例将越来越高。减少烟草导致的大量癌症死亡的一个潜在的重要方法是化学预防。我们的肺癌化学预防计划项目的长期目标是开发化学预防策略，以减少目前和以前吸烟者的高危肺癌发病率。计划项目 将集中于布地奈德(一种糖皮质激素激动剂)、绿茶提取物(多酚E)、肌醇和二氟甲基鸟氨酸(DFMO)的化学预防策略，原因有三：i)它们在啮齿动物模型中显示出高的化学预防效果；ii)它们在致癌的启动后阶段有效；iii)它们有过治疗或饮食给药的历史。我们的计划项目由一组肺癌科学家设计的四个研究项目组成，以解决我们的主要假设--化学预防药物的选择性组合可以防止呼吸道上皮癌变病变的进展和形成。总而言之，计划项目将(1) 进行第二阶段试验，以确定绿茶的有效性和安全性，绿茶是仅次于水的第二种最常用的肺癌化学预防饮料(项目I)；(2)产生关于将细胞生存途径中的标志物用作化学预防试验的中间终点生物标志物的新信息(项目I-III)；(3)促进一项重大的新倡议，发展共聚焦误诊内窥镜检查，作为一种非活检方法来评估化学预防药物的效果(项目I)；(4)通过检查它们抑制肺癌进展的能力，确定在未来的第二阶段试验中结合化学预防药物的科学基础 在腺癌的小鼠模型和上呼吸道鳞状细胞癌的仓鼠模型(项目II-IV)和单一药物的临床试验(项目I)中，从癌前病变到更晚期的病变。

Lung cancer is the leading cause of death in men and women in the United States (160,000 new cases and 157,400 deaths in 2001). Although the relative risk of developing lung cancer declines in smokers who quit, former smokers remain at high risk for at least 5 years. Since smoking cessation is a major public health initiative, former smokers will increasingly account for a high percentage of lung cancer. A potential important approach to reduce the large number of tobacco caused cancer deaths is chemoprevention. The long-term goal o f our Chemoprevention of Lung Cancer Program Project is to develop chemopreventive strategies to reduce the incidents of lung cancer in high-risk current and former smokers. The Program Project will focus its chemoprevention strategies on Budesonide (a glucocorticoid agonist), green tea extracts (Polyphenon E), Myo-inositol, and difiuoromethylornithine (DFMO) for three reasons: i) they exhibit high chemopreventive efficacy in rodent models; ii) they are effective in the post-initiation period of carcinogenesis; and iii) they have a previous history of therapeutic or dietary administration to humans. Our Program Project consists of four research projects designed by a group of lung cancer scientists to address our primary hypothesis--selective combination of chemoprevention agents can prevent the progression and formation ofpreneoplastic lesions in the respiratory epithelium. In summary, the Program Project will (1) conduct a Phase II trial to determine the efficacy and safety of green tea, the second most commonly consumed beverage after water for chemoprevention of lung cancer (Project I); (2) generate new information on the use of markers in cell survival pathways as intermediate endpoint biomarkers for chemoprevention trials (Project I-III); (3) facilitate a major new initiative to develop confocal miscroendoscopy as a non-biopsy method to assess the effect ofchemopreventive agents (Project I); (4) determine the scientific basis for combining chemopreventive agents in future Phase II trials by examining their ability to inhibit progression of preneoplasia to more advanced lesions in a mouse model for adenocarcinoma and a hamster model for upper respiratory squamous cell carcinoma (Project II-IV) and by clinical trials with single agents (Project I).