CHEMOPREVENTION OF LUNG SQUAMOUS CELL CARCINOMA WITH POLYPHENON E

多苯酚 E 化学预防肺鳞状细胞癌

• 批准号: 7590802
• 负责人: YIAN WANG
• 金额: $ 31.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590802
• 关键词: Chemoprevention; Chemopreventive Agent; Clinical Chemoprevention; Clinical Trials; Data; Development; Dysplasia; Epigallocatechin Gallate; Exhibits; Foundations; Goals; Green tea; Human; Hyperplasia; Inbred Strains Mice; Lung Adenocarcinoma; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mouse Strains; Mus; Polyphenon E; Preparation; Rattus; Solid; Squamous Cell Lung Carcinoma; TP53 gene; Testing; Transcription Factor AP-1; Transgenic Mice; cancer chemoprevention; carcinogenesis; inhibitor/antagonist; innovation; lung Carcinoma; lung development; mouse model; mutant; mutant mouse model; pre-clinical; prevent; public health relevance

DESCRIPTION (provided by applicant): Although many mouse models of lung adenocarcinoma exist, there is no mouse lung squamous cell carcinoma model that has been validated for use in preclinical lung cancer chemoprevention studies. Since most clinical chemoprevention trials of lung cancer are performed in subjects with bronchial dysplasia, development of a lung squamous cell carcinoma mouse model becomes one of the highest priorities. We have shown that lung squamous cell carcinomas can be induced chemically in several strains of mice (Wang et al. 2004) and that green tea polyphenols exhibit a significant efficacy against the development of lung squamous cell carcinomas (preliminary data section). In this proposal, we will use a standardized green tea preparation called Polyphenon E (PE) and its major component, EGCG. The overall objective of this proposal is to determine the efficacy of green tea polyphenols in a mouse lung squamous cell carcinoma model and to determine the molecular mechanism that underlies the efficacy of green tea polyphenols in this new mouse model. We hypothesize that green tea polyphenols will prevent chemically induced lung squamous cell carcinoma development and progression in a mutant p53 mouse model, and the chemopreventive effect of green tea polyphenols is, in part, mediated by AP-1. Three aims were proposed to test this hypothesis. Aim 1 will evaluate the effect of green tea polyphenols on lung squamous cell carcinoma carcinogenesis in a p53 mutant transgenic mouse lung carcinoma model. Aim 2 will determine if blockade of AP-l activity will inhibit lung squamous cell carcinoma development and determine if AP-l activity is required for the chemopreventive efficacy of green tea polyphenols. Aim 3 will perform phenotypic profiling of green tea polyphenols' efficacy against lung squamous cell carcinoma development in inbred strains of mice. The results from this proposal will provide a solid foundation for clinical trials of green tea polyphenols as a lung cancer chemopreventive agent. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine the efficacy of green tea polyphenols in a mouse lung squamous cell carcinoma model and to determine the molecular mechanism that underlies the efficacy of green tea polyphenols in this new mouse model. The results from this proposal will provide a solid foundation for clinical trials of green tea polyphenols as a lung cancer chemopreventive agent.

描述（由申请人提供）：尽管存在许多肺腺癌的小鼠模型，但没有小鼠肺鳞状细胞癌模型已得到验证，用于用于临床前肺癌化学预防研究。由于大多数肺癌的临床化学预防试验都是在支气管异常增生的受试者中进行的，因此肺鳞状细胞癌小鼠模型的发展成为最高优先事项之一。我们已经表明，可以在几种小鼠菌株中化学诱导肺鳞状细胞癌（Wang等，2004），并且绿茶多酚对肺鳞状细胞癌的发展具有显着的功效（初步数据部分）。在此提案中，我们将使用称为Polyphenon E（PE）及其主要成分EGCG的标准化绿茶制剂。该提案的总体目的是确定绿茶多酚在小鼠肺鳞状细胞癌模型中的功效，并确定在这种新小鼠模型中绿茶多酚的功效的分子机制。我们假设绿茶多酚将防止突变p53小鼠模型中化学诱导的肺鳞状细胞癌发育和进展，并且绿茶多酚的化学预防作用部分由AP-1介导。提出了三个目的来检验这一假设。 AIM 1将评估绿茶多酚对p53突变的转基因小鼠肺癌模型中肺鳞状细胞癌的癌变的影响。 AIM 2将确定AP-L活性的阻滞是否会抑制肺鳞状细胞癌的发育，并确定绿茶多酚的化学预防疗效是否需要AP-L活性。 AIM 3将对绿茶多酚针对肺鳞状细胞癌在小鼠的近交菌株中的发育进行表型分析。该提案的结果将为绿茶多酚作为肺癌化学预防剂的临床试验奠定坚实的基础。公共卫生相关性：该提案的目的是确定绿茶多酚在小鼠肺鳞状细胞癌模型中的疗效，并确定在该新小鼠模型中绿色茶多酚的功效的分子机制。该提案的结果将为绿茶多酚作为肺癌化学预防剂的临床试验奠定坚实的基础。