Chemoprevention of Lung Cancer

肺癌是美国男性和女性死亡的主要原因（2001年有160，000例新发病例和157，400例死亡）。虽然戒烟者患肺癌的相对风险下降，但前吸烟者仍处于高风险状态至少5年。由于戒烟是一项重大的公共卫生举措，因此前吸烟者在肺癌中所占的比例越来越高。化学预防是减少大量烟草引起的癌症死亡的一个潜在的重要方法。我们的肺癌化学预防计划项目的长期目标是制定化学预防策略，以减少高危吸烟者和前吸烟者的肺癌发病率。方案项目 将其化学预防策略集中在布地奈德（一种糖皮质激素激动剂）、绿色茶提取物（Polyphenon E）、肌醇和二氟甲基鸟氨酸（DFMO）上，原因有三：i）它们在啮齿动物模型中表现出高的化学预防功效; ii）它们在癌发生的后起始期有效;和iii）它们具有对人类的治疗或饮食施用的先前历史。我们的计划项目包括四个研究项目，由一组肺癌科学家设计，以解决我们的主要假设-选择性联合化学预防剂可以防止呼吸道上皮癌前病变的进展和形成。总而言之，该计划项目将（1） 进行第二阶段试验，以确定绿色茶的有效性和安全性，绿茶是继水之后第二种最常饮用的肺癌化学预防饮料（项目I）;（2）产生关于使用细胞存活途径中的标志物作为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）促进一项主要的新倡议，开发共聚焦显微内窥镜作为一种非活检方法，以评估化学预防剂的效果（项目I）;（4）通过检查化学预防剂抑制肿瘤进展的能力，确定在未来II期试验中联合使用化学预防剂的科学依据。 在腺癌小鼠模型和上呼吸道鳞状细胞癌仓鼠模型中（项目II-IV），以及通过单药临床试验（项目I），研究了从癌前病变到更晚期病变的肿瘤发生率。

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).