Antiangiogenic properties of sweet leaf tea extract

描述（由申请人提供）：研究人员在基于人体组织的血管生成实验中发现中国甜叶茶（Rubus suavissimus）的一种特定提取物具有抗血管生成作用，并观察到将该提取物腹腔注射到荷瘤大鼠体内时，对肿瘤生长有明显的抑制作用。初步的细胞毒性评估发现，这种抗血管生成提取物对人类癌细胞系没有明显的细胞毒性。没食子酸已被确定为提取物抗血管生成活性的部分原因之一。进一步的测试揭示了一个令人惊讶的结果——含没食子酸的提取物在抑制血管生成方面比纯没食子酸强10倍，这表明有其他可能更有效的抑制剂参与其中。通过简单、可重复、一步柱层析的方法，将该水萃取物的所有有效的抗血管生成成分完全回收为一种基本精制的叶萃取物，仅占干叶的6% （w/w）。进一步细分这一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，研究人员建议鉴定这些抗血管生成化合物，制定精制提取物生产的质量控制方案，评估体外和体内的相对毒性，确定小鼠和大鼠模型（胰腺癌）中阻止肿瘤生长的功效，并探索作用机制（例如抗vegf）。当这些具体目标在R21中实现时，将在R01中进一步研究具有潜在口服生物利用度、无毒、高活性抗血管生成成分（已被证明可抑制人类血管生长）的概念，该概念将进一步确定作用机制，表征所定义的提取物产品，并进行必要的毒理学研究，以准备申请IND。高度活跃的抗血管生成成分（被证明可以抑制人类血管的生长）是一个真正令人兴奋的想法。这项研究一旦成功完成，将为使用一种新的饮食方法进行癌症靶向治疗的临床评估奠定基础。

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.