Chemoprevention of lung cancer with red ginseng extracts

* 描述(由申请人提供)： 这项提案的总体目标是将红参提取物(RGE)及其关键活性成分(KAC)作为一种有效的肺癌化学预防药物在临床前进行表征。在一项初步研究中，我们证明了红参对A/J小鼠肺癌的化学预防作用。我们假设人参可以防止化学诱导的肺腺癌和鳞状细胞癌在突变的小鼠模型中形成，这种突变的小鼠在人类肺癌中常见的基因变化。为了检验这一假说，本文提出了四个具体目标。目的1通过体外活性导向分离分离红参的关键活性成分，辅以测定红参的肠道吸收潜力。目的2在转基因小鼠肺腺癌模型中评价RGE及其KAC在肺腺癌发生中的作用。目的研究RGE及其KAC对p53基因突变小鼠肺鳞状细胞癌发生的影响。AIM 4将对RGE及其KAC进行药代动力学和生物药学表征。这一建议是及时和重要的，因为未来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有效性和生物药学特性，如生物利用度和药动学特征。此外，我们将使用新开发的肺腺癌和肺鳞癌的突变小鼠肺肿瘤模型，该模型既有组织病理学特征，也有人类肺癌发生过程中观察到的遗传变化。这一建议的结果将为人参作为肺癌化学预防药物的临床试验提供坚实的基础。 公共卫生相关性： 项目简介我们建议将红参提取物(RGE)作为一种有效的肺癌化学预防药物在临床前进行表征。体外实验表明，人参具有抑制肿瘤细胞增殖和诱导肿瘤细胞凋亡的作用。在体内，人参已被证明在包括肺在内的各种器官部位抑制啮齿动物的癌症发生。我们将通过体外活性导向分离分离红参的关键活性成分，并辅之以测定其肠道吸收潜力，在具有人类肺癌常见基因变化的转基因小鼠肺癌模型中评价人参对肺癌发生的影响，并对红参及其关键活性成分进行药代动力学和生物药学研究。我们认为，这些拟议的研究具有重要意义，因为未来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有效性和生物药学特性，如生物利用度和药动学特征。

* 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.