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Development of the haparan sulfate-based anti-cancer drugs

硫酸乙酰肝素抗癌药物的研制

基本信息

批准号：
12557214
负责人：
SUGAHARA Kazuyuki
金额：
$ 8.26万
依托单位：
KOBE PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

The major results can be classified into the following three categories.1)The detailed substrate specificity was revealed for human heparanase that is involved in the tumor invasion and metastasis, which has provided the basic knowledge for developing the early diagnosis of cancers.2)In addition to the EXT1/EXT2 complex; the requirement of the aglycon moiety for the acceptor substrate for the above enzyme complex, which catalyzes the polymerization of a heparan backbone, was demonstrated, and the polymerization was achieved for the first time. Furthermore, the recombinant human EXTL2 protein, which is likely involved in the regulation of heparan sulfate synthesis, was crystallized, and the crystallographic data have provided a clue to investigate the molecular mechanism of heparan sulfate synthesis.3)It was demonstrated that the so-called heparin-binding growth factors, which utilize heparan sulfate as a co-receptor, can interact specifically also with chondroitin sulfate chains containing the "E" disaccharide units. The results suggested that chondroitin sulfate can also be applicable to the development of anti-cancer drugs. In addition, the chondroitin sulfate chain of an amyloid precuresorprotein appican produced by rat C6 glyoma cells, unlike the chondroitin sulfate chain of appican expressed in neuronal cells, was shown to contain the "E" units and specifically interact with heparin-binding growth factors. These findings suggested that the chondroitin sulfate chain produced by glial cells may regulate the functions of neuronal cells.

主要结果可分为以下三类：1)揭示了参与肿瘤侵袭和转移的人肝素酶的底物专一性，为肿瘤的早期诊断提供了基础知识。2)除了EXT1/Ext2复合体之外，还证明了上述催化肝素骨架聚合的酶复合体对受体底物的苷元部分的需求，并首次实现了聚合。此外，对可能参与硫酸乙酰肝素合成调控的重组人EXTL2蛋白进行了结晶，结晶数据为研究硫酸乙酰肝素合成的分子机制提供了线索。3)研究表明，以硫酸乙酰肝素为共受体的所谓的肝素结合生长因子也可以与含有E双糖单元的硫酸软骨素特异地相互作用。结果表明，硫酸软骨素也可用于抗癌药物的开发。此外，由大鼠C6细胞产生的淀粉样前体蛋白appican的硫酸软骨素链，与神经细胞表达的appican的硫酸软骨素链不同，被证明含有“E”单位，并与肝素结合生长因子特异性地相互作用。提示神经胶质细胞产生的硫酸软骨素链可能对神经细胞的功能有调节作用。