Developing a Post-carcinogen Lung Cancer Chemopreventive Agent

描述（由申请人提供）：由于既往吸烟者患肺癌的风险较高，并且所有新发肺癌发病率中约有一半发生在既往吸烟者中，因此迫切需要开发安全有效的化学预防剂来帮助既往吸烟者控制这种致命疾病。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，帮助前吸烟者预防或延迟肺癌的发展。 我们最近的研究结果强烈支持这样一种观点，即卡瓦胡椒是南太平洋岛屿的一种长期饮料，有希望通过抑制NF-κ B活化来预防致癌后肺癌的发展。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。这种优化还可以导致改进的安全性。 因此，本申请的目的是改善卡瓦的致癌物后化学预防功效，建立化学预防卡瓦的安全性，鉴定与商业卡瓦相关的潜在肝毒性的起源，并探索负责卡瓦诱导的化学预防的机制，如NF-κ B抑制。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物后化学预防功效，并确定最具化学预防功效的组分抑制肺病变进展为腺癌的功效目的2。确定与市售卡瓦Aim 3相关的肝毒性的来源。表征最具化学预防性的卡瓦制剂中的主要化学品，用于未来化学预防性卡瓦产品目标4的QC/QA。确定最具化学预防性的卡法根制剂对关键信号传导途径（包括NF-κ B途径）的作用在实现这些目标后，我们将（a）鉴定出比现有商业产品更有效和更安全的卡法根制剂，（B）确定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的来源归因于非极性级分;（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;和（e）提供了关于kava诱导的致癌物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导致死亡的主要原因。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，可以防止NNK/B[a] P诱导的A/J小鼠的肺癌发生，其结果预计将为开发一种化学预防CAM模式奠定基础，这将有助于前吸烟者预防/延迟肺癌。

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.