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试验中发现，中国甜叶茶(Rubus Suavissimus)的一种明确的提取物具有抗血管生成作用，并观察到该提取物在腹膜内注射到荷瘤大鼠身上时，对肿瘤生长有明显的抑制作用。初步的细胞毒性评价发现，该抗血管生成提取物对人癌细胞株没有明显的细胞毒性。没食子酸已被确定为该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--含有没食子酸的提取物在抑制血管生成方面的效力是纯没食子酸的10倍，这表明其他可能更有效的抑制剂参与了这一过程。对这种水提物进行分级，可在简单、可重复的一步柱层析法中将所有有效的抗血管生成成分完全回收到实质上精制的叶提取物中，仅占干燥叶的6%(w/w)。对这一精制提取物的进一步细分证实了其他抗血管生成活性成分的存在。基于这些结果，研究人员建议鉴定这些抗血管生成的化合物，制定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，确定其在小鼠和大鼠模型(胰腺癌)中阻止肿瘤生长的有效性，并探索其作用机制(如抗血管内皮生长因子)。当这些特定目标在R21中实现时，具有潜在的口服生物利用度、无毒、高活性抗血管生成成分(经证实可防止人类血管生长)的概念将在R01中得到进一步研究，该R01将进一步定义作用机制，表征已定义的提取物产品，并进行必要的毒理学研究，以期提交IND。拥有一种潜在的口服生物利用、无毒、高活性的抗血管生成成分(经证实可防止人类血管生长)的概念本身就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.