Chemoprevention of lung cancer with red ginseng extracts

* 描述（由申请人提供）： 本提案的总体目标是表征红参提取物（RGE）及其关键活性成分（KAC）作为一种有效的肺癌化学预防剂的临床前。在初步研究中，我们证明了红参在A/J小鼠肺肿瘤发生的化学预防中具有很强的功效。我们假设，人参将防止化学诱导的肺腺癌和鳞状细胞癌形成的突变小鼠模型与常见的人类肺癌的遗传变化。提出了四个具体目标来检验这一假设。目的1通过体外活性导向的色谱分离技术，结合小肠吸收能力的测定，确定红参中的关键活性成分。目的2：在转基因小鼠肺腺癌模型中评价RGE及其KAC对肺腺癌癌变的影响，该模型具有在人类肺癌中常见的遗传改变。目的3研究RGE及其KAC对p53突变小鼠肺鳞癌发生的影响。目的4：研究RGE及其KAC的药代动力学和生物药剂学特性。这一建议是及时和重要的，因为未来的人参对人类肺癌的化学预防临床试验需要积极的临床前表征其疗效和生物制药特征，如生物利用度和药代动力学特征。此外，我们将使用一种新开发的突变小鼠肺肿瘤模型的肺腺癌和肺鳞状细胞癌，这两个股票的组织病理学特征和遗传改变中观察到的人类肺癌。本研究结果将为人参作为肺癌化学预防剂的临床试验提供坚实的基础。 公共卫生相关性： 项目叙述我们建议将红参提取物（RGE）作为一种有效的肺癌化学预防剂进行临床前表征。体外实验表明，人参抑制肿瘤细胞系的细胞增殖并诱导凋亡。在体内，人参已被证明可以抑制啮齿动物在各种器官部位（包括肺）的致癌作用。我们将通过体外活性导向的分级色谱分离，辅以测量其肠道吸收潜力，确定红参的关键活性成分，在转基因小鼠肺癌模型中评估人参对肺癌发生的影响，并在人类肺癌中常见的遗传变化，并进行药代动力学和生物制药特征的红参及其关键活性成分。我们认为，拟议的研究是重要的，因为未来的人参对人类肺癌的化学预防临床试验需要积极的临床前表征其疗效和生物制药特性，如生物利用度和药代动力学特征。

* DESCRIPTION (provided by applicant): The overall objective of this proposal is to characterize red ginseng extract (RGE) and its key active components (KAC) preclinically as a potent lung cancer chemopreventive agent. In a preliminary study, we demonstrated a strong efficacy of red ginseng in chemoprevention against lung tumor development in A/J mice. We hypothesize that ginseng will prevent chemically induced lung adenocarcinoma and squamous cell carcinoma formation in a mutant mouse model with genetic changes commonly seen in human lung cancers. Four specific aims are proposed to test this hypothesis. Aim 1 will identify the key active components of red ginseng via in vitro activity- guided fractionation chromatographic separation supplemented by measuring their intestinal absorption potentials. Aim 2 will evaluate the effect of RGE and its KAC on lung adenocarcinoma carcinogenesis in a transgenic mouse lung adenocarcinoma model with genetic changes commonly seen in human lung cancers. Aim 3 will determine the effect of RGE and its KAC on lung squamous cell carcinoma development in p53 mutant mice. Aim 4 will perform pharmacokinetic and biopharmaceutical characterizations of RGE and its KAC. This proposal is timely and significant since future chemoprevention clinical trials of ginseng against lung cancer in humans require vigorous preclinical characterization of its efficacy and biopharmaceutical characteristics such as bioavailability and pharmacokinetic profile. Furthermore, we will use a newly developed mutant mouse lung tumor models of both lung adenocarcinoma and lung squamous cell carcinoma, which shares both histopathological features and genetic alterations observed in human lung carcinogenesis. The results from this proposal will provide a solid foundation for clinical trials of ginseng as a lung cancer chemopreventive agent. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE We propose to characterize red ginseng extracts (RGE) preclinically as a potent lung cancer chemopreventive agent. In vitro experiments have shown that ginseng inhibits cell proliferation and induces apoptosis in tumor cell lines. In vivo, ginseng has been shown to inhibit rodent carcinogenesis in various organ sites including the lung. We will identify the key active components of red ginseng via in vitro activity-guided fractionation chromatographic separation supplemented by measuring their intestinal absorption potentials, evaluate the effect of ginseng on lung carcinogenesis in a transgenic mouse lung carcinoma model with genetic changes commonly seen in human lung cancers, and perform pharmacokinetic and biopharmaceutical characterizations of red ginseng and its key active components. We believe that the proposed studies are significant because future chemoprevention clinical trials of ginseng against lung cancer in humans require vigorous preclinical characterization of its efficacy and biopharmaceutical characteristics such as bioavailability and pharmacokinetic profile.