Antiangiogenic properties of sweet leaf tea extract

甜叶茶提取物的抗血管生成特性

• 批准号: 7256758
• 负责人: ZHIJUN LIU
• 金额: $ 26.46万
• 依托单位: LOUISIANA STATE UNIV AGRICULTURAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256758
• 关键词: Accounting; Analytical Chemistry; Angiogenesis Inhibition; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Apoptosis; Applications Grants; Bioavailable; Biological Assay; Biomass; Blood Vessels; Botanicals; Brain Neoplasms; Breast; Cancer cell line; Caspase; Cell Cycle; Cell Line; Cell Proliferation; Chinese People; Clinical Research; Clinical Trials; Colon; Column Chromatography; Crude Extracts; Cytochromes; Data; Development; Dose; Evaluation; Fractionation; Future; Gallic acid; Gene Proteins; Genus Cola; Goals; Grant; Growth; Human; Human Cell Line; Implant; In Vitro; Inflammation; Investigation; Knowledge; Left; MX-1; Malignant Neoplasms; Measures; Mediating; Methodology; Methods; Modeling; Mus; Nature; Nude Mice; One-Step dentin bonding system; Oral; Pancreas; Pancreatic carcinoma; Phosphorylation; Pilot Projects; Plant Extracts; Plant Leaves; Procedures; Production; Property; Prostate; Protocols documentation; Quality Control; Range; Rattus; Recovery; Relative (related person); Reproducibility; Research; Research Personnel; Rodent; Route; Solid Neoplasm; Solvents; Staging; TdT-Mediated dUTP Nick End Labeling Assay; Tea; Techniques; Testing; Thinking; Tissues; Toxic effect; Toxicology; Treatment Protocols; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; aqueous; base; bevacizumab; cancer therapy; cell growth; concept; cytotoxic; cytotoxicity; day; dosage; eicosanoid metabolism; follow-up; human tissue; in vivo; inhibitor/antagonist; neoplastic cell; novel; pancreatic neoplasm; pre-clinical; prevent; research clinical testing; scale up; tumor; tumor growth

DESCRIPTION (provided by applicant): The investigators have discovered that a defined extract of Chinese sweet leaf tea (Rubus suavissimus) is anti-angiogenic in a human-tissue based angiogenesis assay and have observed potent tumor growth inhibition of the extract when injected intraperitoneally to a tumor-bearing rat. Preliminary cytotoxicity evaluation found this anti-angiogenic extract was not significantly cytotoxic to human cancer cell lines. Gallic acid has been identified as one of the components that is partially responsible for the extract's antiangiogenic activity. Further testing has revealed a surprising result - the gallic acid-containing extract is 10-fold more potent than pure gallic acid in producing inhibition of angiogenesis, indicative of involvement of other, perhaps more potent inhibitors. Fractionation of this aqueous extract resulted in the complete recovery, in a simple, repeatable, one-step column chromatography method, of all the potent antiangiogenic ingredients into a substantially refined leaf extract, accounting for only 6% (w/w) of the dried leaves. Further subfractionation of this refined extract confirmed the existence of other active anti-angiogenic components. Based on these results the investigators propose to identify these anti-angiogenic compounds and develop a quality control protocol for production of the refined extract, assess relative toxicity in vitro and in vivo, determine the efficacy in stopping tumor growth in mice and rat models (pancreatic carcinoma), and explore mechanisms of action (e.g. anti-VEGF). When these specific aims are accomplished in this R21, the very concept of having a potential orally bioavailable, nontoxic, highly active anti-angiogenic component (proven against growth of HUMAN blood vessels) will be further investigated in an R01 that will further define the mechanisms of action, characterize the defined extract product, and conduct necessary toxicology studies in anticipation of filing an IND. The very concept of having a potential orally bioavailable, nontoxic, highly active anti-angiogenic component (proven against growth of HUMAN blood vessels) is a truly exciting thought. This research, when successfully completed, will set the stage for clinical evaluation of a targeted therapy for cancer using a novel, dietary approach.

描述（由申请人提供）：研究人员发现，在基于人体组织的血管生成试验中，中国甜叶茶（Rubus suavissimus）的确定提取物具有抗血管生成作用，并且当向荷瘤大鼠腹腔内注射时，观察到提取物的有效肿瘤生长抑制作用。初步的细胞毒性评价发现，这种抗血管生成提取物对人类癌细胞系没有显著的细胞毒性。没食子酸已被确定为部分负责提取物的抗血管生成活性的组分之一。进一步的测试已经揭示了一个令人惊讶的结果-含没食子酸的提取物在产生血管生成抑制方面比纯没食子酸强10倍，表明涉及其他可能更有效的抑制剂。该水提取物的分级导致在一个简单的，可重复的，一步柱色谱法中的所有有效的抗血管生成成分的完全回收，基本上精制的叶提取物，仅占6%（w/w）的干燥叶。进一步亚分级的这种精制提取物证实了其他活性抗血管生成成分的存在。基于这些结果，研究人员提出鉴定这些抗血管生成化合物，并开发用于生产精制提取物的质量控制方案，评估体外和体内的相对毒性，确定在小鼠和大鼠模型（胰腺癌）中停止肿瘤生长的功效，并探索作用机制（例如抗VEGF）。当这些特定目标在该R21中实现时，具有潜在的口服生物可利用的、无毒的、高活性的抗血管生成组分的概念（经证明可抑制人体血管生长）将在R 01中进一步研究，R 01将进一步定义作用机制，表征定义的提取物产品，并进行必要的毒理学研究，以预期提交IND。具有潜在的口服生物可利用性，无毒，高活性抗血管生成成分（经证实可抑制人体血管生长）是一个真正令人兴奋的想法。这项研究成功完成后，将为使用新型饮食方法进行癌症靶向治疗的临床评估奠定基础。