Developing a Post-carcinogen Lung Cancer Chemopreventive Agent

开发致癌后肺癌化学预防剂

• 批准号: 8509621
• 负责人: CHENGGUO XING
• 金额: $ 20万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509621
• 关键词: A/J Mouse; Adenocarcinoma; Animal Model; Basic Science; Benzo(a)pyrene; Beverages; Butanones; Cancer Biology; Carcinogens; Cause of Death; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Trials; Complementary and alternative medicine; Consumption; Data; Development; Disease; Dose; Evaluation; Female; Food; Foundations; Fractionation; Future; Goals; Grant; Growth; Hepatocyte; Hepatotoxicity; Human; In Vitro; Inbred F344 Rats; Incidence; Kava; Lead; Lesion; Lipopolysaccharides; Liver; Lung; Lung Adenoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modality; Modeling; Molecular Target; Monkeys; Mus; NF-kappa B; Oral; Outcome; Pacific Islands; Pathology; Pathway interactions; Pharmaceutical Chemistry; Preparation; Preventive; Proteins; Quality Control; Quality of life; Rattus; Regimen; Research; Resources; Risk; STAT3 gene; Safety; Sequence Determination; Signal Pathway; Smoker; Structure of parenchyma of lung; Testing; Time; Toxic effect; Toxicology; Transcription Factor AP-1; United States National Institutes of Health; Validation; Work; Xenograft procedure; adenoma; base; cancer chemoprevention; high risk; improved; in vivo; insight; lung tumorigenesis; multidisciplinary; pre-clinical research; prevent; public health relevance; research study; response; tumor progression; tumorigenesis; validation studies

DESCRIPTION (provided by applicant): Since former smokers are at an elevated risk to develop lung cancer and about half of all new lung cancer incidences are among former smokers, there is an urgent need to develop safe and efficacious chemopreventive agents to help former smokers control this deadly disease. Our long-term goal is to develop a Complementary and Alternative Medicine (CAM) modality based on natural food and beverages that will help former smokers to prevent or delay lung cancer development. The results of our recent studies strongly support the notion that kava, a long-standing beverage in the South Pacific Islands, is promising to prevent post-carcinogen lung cancer development, potentially through suppressing NF-kB activation. Our preliminary data also suggest that kava's chemopreventive efficacy can be improved by enriching its chemopreventive constituents. Such optimization may also lead to improved safety. The objectives of this application, therefore, are to improve kava's post-carcinogen chemopreventive efficacy, to establish chemopreventive kava's safety, to identify the origin of potential hepatotoxicity associated with commercial kava, and to explore the mechanisms, such as NF-kB inhibition, that are responsible for kava-induced chemoprevention. Specifically, the following four Aims will be pursued: Aim 1. Determine the post-carcinogen chemopreventive efficacy of kava fractions against lung adenoma formation and establish the efficacy of the most chemopreventive fraction to inhibit lung lesion progression to adenocarcinoma Aim 2. Identify the origin of hepatotoxicity associated with commercial kava Aim 3. Characterize major chemicals in the most chemopreventive kava preparation for QC/QA of the future chemopreventive kava product Aim 4. Determine the effects of the most chemopreventive kava preparation on key signaling pathways, including the NF-kB pathway Upon accomplishing these aims, we will have (a) identified a kava preparation more efficacious and safer than the existing commercial product, (b) established its efficacy to prevent lung cancer progression to adenocarcinomas, (c) ascribed the origin of hepatoxicity associated with commercial kava to the non-polar fraction; (d) characterized active/signature chemicals for better QC/QA of the future kava product; and (e) provided mechanistic insights concerning key signaling pathways and possibly the molecular targets for kava-induced post-carcinogen lung cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of death among all malignancies. Former smokers are at a high risk to develop lung cancer. This research focuses on identifying a kava-based safe CAM modality that can prevent NNK/B[a]P-induced lung tumorigenesis in A/J mice with post-carcinogen regimen, the outcome of which is expected to set the foundation for developing a chemopreventive CAM modality that will help former smokers to prevent/delay lung cancer.

描述（由申请人提供）：由于前吸烟者患肺癌的风险较高，并且约一半新发肺癌发生在前吸烟者中，因此迫切需要开发安全有效的化学预防药物来帮助前吸烟者控制肺癌这种致命的疾病。我们的长期目标是开发一种基于天然食品和饮料的补充和替代医学（CAM）模式，帮助戒烟者预防或延缓肺癌的发展。 我们最近的研究结果有力地支持了这样一种观点，即卡瓦酒是南太平洋群岛的一种历史悠久的饮料，有望通过抑制 NF-kB 激活来预防致癌物后肺癌的发展。我们的初步数据还表明，卡瓦的化学预防功效可以通过丰富其化学预防成分来提高。这种优化还可以提高安全性。 因此，本申请的目的是提高卡瓦的致癌物后化学预防功效，确定卡瓦化学预防的安全性，确定与商业卡瓦相关的潜在肝毒性的根源，并探索其机制，例如 NF-kB 抑制，负责卡瓦诱导的化学预防。具体而言，将追求以下四个目标： 目标 1. 确定卡瓦组分对肺腺瘤形成的致癌后化学预防功效，并确定最具化学预防作用的组分抑制肺病变进展为腺癌的功效 目标 2. 确定卡瓦组分的起源与商业卡瓦相关的肝毒性 目标 3. 表征最具化学预防性的卡瓦制剂中的主要化学物质，以用于质量控制/质量保证未来化学预防卡瓦产品 目标 4. 确定最具化学预防作用的卡瓦制剂对关键信号通路（包括 NF-kB 通路）的影响 实现这些目标后，我们将 (a) 确定一种比现有商业卡瓦制剂更有效、更安全的卡瓦制剂产品，(b) 确定了其预防肺癌进展为腺癌的功效，(c) 将与商业卡瓦相关的肝毒性起源归因于非极性部分； (d) 表征活性/特征化学品，以更好地对未来卡瓦产品进行质量控制/质量保证； (e) 提供了有关卡瓦诱导的致癌后肺癌化学预防的关键信号通路和可能的分子靶点的机制见解。 公共卫生相关性：肺癌是所有恶性肿瘤中死亡的主要原因。以前吸烟的人患肺癌的风险很高。这项研究的重点是确定一种基于卡瓦的安全 CAM 模式，该模式可以预防采用致癌物后治疗方案的 A/J 小鼠中 NNK/B[a]P 诱导的肺部肿瘤发生，其结果预计将为开发化学预防 CAM 模式将帮助戒烟者预防/延缓肺癌。