Chemoprevention of lung cancer with red ginseng extracts

红参提取物对肺癌的化学预防

• 批准号: 8133545
• 负责人: MING YOU
• 金额: $ 46.21万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133545
• 关键词: A/J Mouse; Affinity Chromatography; Alleles; Apoptosis; Biological Assay; Biological Availability; Biological Products; Caco-2 Cells; Cell Proliferation; Cell model; Characteristics; Chemoprevention; Chemopreventive Agent; Clinical Research; Clinical Trials; Deletion Mutation; Development; Dominant-Negative Mutation; Dose; Drug Kinetics; Foundations; Fractionation; Future; Ginseng Preparation; High Pressure Liquid Chromatography; Human; In Vitro; Intestinal Absorption; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Measures; Methods; Modeling; Mus; Mutant Strains Mice; Mutation; Organ; Preventive; Regimen; Research Design; Rodent; Screening procedure; Silicones; Site; Solid; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Testing; Time; Transgenic Mice; Tumor Cell Line; base; carcinogenesis; experience; in vitro activity; in vivo; liquid chromatography mass spectrometry; lung Carcinoma; lung carcinogenesis; mouse model; mutant mouse model; pre-clinical; preclinical study; prevent; public health relevance; research study; solvent extraction; tumor

* 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.

* 描述（由申请人提供）： 该提案的总体目标是在临床前表征红参提取物（RGE）及其关键活性成分（KAC）作为有效的肺癌化学预防剂的作用。在一项初步研究中，我们证明了红参在化学预防 A/J 小鼠肺部肿瘤发展方面的强大功效。我们假设，在具有人类肺癌中常见遗传变化的突变小鼠模型中，人参将预防化学诱导的肺腺癌和鳞状细胞癌的形成。提出了四个具体目标来检验这一假设。目标 1 将通过体外活性引导的分级色谱分离并通过测量其肠道吸收潜力来鉴定红参的关键活性成分。目标 2 将在转基因小鼠肺腺癌模型中评估 RGE 及其 KAC 对肺腺癌癌变的影响，该模型具有人类肺癌中常见的遗传变化。目标 3 将确定 RGE 及其 KAC 对 p53 突变小鼠肺鳞状细胞癌发展的影响。目标 4 将进行 RGE 及其 KAC 的药代动力学和生物制药表征。该提议是及时且重要的，因为未来人参抗肺癌的化学预防临床试验需要对其功效和生物制药特性（例如生物利用度和药代动力学特征）进行严格的临床前表征。此外，我们将使用新开发的肺腺癌和肺鳞状细胞癌突变小鼠肺肿瘤模型，其具有在人类肺癌发生过程中观察到的组织病理学特征和遗传改变。该提案的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： 项目叙述我们建议在临床前将红参提取物（RGE）描述为一种有效的肺癌化学预防剂。体外实验表明，人参能抑制肿瘤细胞系的细胞增殖并诱导细胞凋亡。在体内，人参已被证明可以抑制啮齿动物各个器官部位（包括肺部）的致癌作用。我们将通过体外活性引导的分级色谱分离并测量其肠道吸收潜力来鉴定红参的关键活性成分，并在具有人类肺部常见遗传变化的转基因小鼠肺癌模型中评估人参对肺癌发生的影响癌症，并进行红参及其关键活性成分的药代动力学和生物制药表征。我们认为，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对其功效和生物制药特性（例如生物利用度和药代动力学特征）进行强有力的临床前表征。