Analysis of the mechanisms of expression and function of endostatin, a novel anti-cancer medicine derived from basement membrane collagen.

内皮抑素是一种内源性血管生成抑制物，具有较强的抗癌活性。在小鼠肿瘤模型中，内皮抑素具有抑制肿瘤进展、抑制肿瘤转移和诱导肿瘤消退的作用。本研究的最终目的是从分子水平上阐明内皮抑素的作用机制，为抗癌新药的开发做出贡献。在2002-2003年间，我们实现了以下进展。据报道，血清内皮抑素水平与癌症的进展呈正相关。因此，我们检测了人血清中内皮抑素相关蛋白的血管生成抑制活性。用抗内皮抑素免疫亲和层析柱从人血清中分离得到4个内皮抑素相关片段。4个片段的重组蛋白在内皮细胞迁移实验中显示了抑制活性。在人脑胶质瘤组织匀浆中检测到与内皮抑素抗体反应的25 kDa片段。组织内皮抑素(25 kDa片段)水平与胶质瘤恶性程度呈正相关。此外，通过对内皮抑素的功能研究发现，内皮抑素对某些基质金属蛋白酶具有抑制活性。血管生成抑制剂被认为是治疗类风湿性关节炎的一种潜在方法。我们评价了内皮抑素在两种不同类风湿关节炎动物模型上的疗效，证明内皮抑素是治疗类风湿关节炎的一种有前途的药物。

Endostatin is an endogenous angiogenesis inhibitor and showed quite strong anti-cancer activity. In mouse tumor model, endostatin inhibits tumor progression, tumor metastasis and induces tumor regression The final goal of this research is to elucidate the functional mechanisms of endostatin on molecular level, then to contribute the development of new anti-cancer drugs. During 2002 to 2003, we achieved those progression described below.It was reported that serum level of endostatin Was positively correlated to the progression of cancer. Therefore, we measured angiogenesis inhibitory activity of endostatin-related proteins in human serum. Four endostatin-related fragments were isolated from human serum by anti-endostatin immuno-affinity colum. Recombinant proteins for four fragments revealed inhibitory activities in endothelial cell migration assay. We detected 25kDa fragment reacted with anti-endostatin antibody in the homogenates of human glioma tissues. The levels of tissue endostatin (25kDa fragment) and malignancy grades in gliomas showed the positive correlation. Also, we discovered that endostatin has inhibitory activity against some matrix metalloproteinases through the examination of functional study of endostatin. Angiogenesis inhibitors were considered to be a potential therapy of rheumatod arthritis. We estimated the efficacy of endostatin in two different animal models of rhematoid arthritis and endostatin was proved to be a promising medicine for rhematoid arthritis.