Development of the haparan sulfate-based anti-cancer drugs

主要结果可归纳为以下三个方面：1）揭示了参与肿瘤侵袭和转移的人乙酰肝素酶的详细底物特异性，为发展肿瘤的早期诊断提供了基础知识。证明了对于催化乙酰肝素骨架聚合的上述酶复合物的受体底物需要糖苷配基部分，并首次实现了聚合。此外，重组人EXTL 2蛋白，这可能是参与硫酸乙酰肝素合成的调控，结晶，和晶体学数据提供了一个线索，研究硫酸乙酰肝素合成的分子机制。3）这表明，所谓的肝素结合生长因子，利用硫酸乙酰肝素作为共受体，也可与含有"E"二糖单元的硫酸软骨素链特异性相互作用。结果提示硫酸软骨素也可用于抗癌药物的开发。此外，硫酸软骨素链的淀粉样前尿素蛋白appican大鼠C6胶质瘤细胞产生的，不同的硫酸软骨素链appican在神经元细胞中表达，显示含有"E"单位，并特别与肝素结合生长因子相互作用。这些结果表明，神经胶质细胞产生的硫酸软骨素链可能调节神经细胞的功能。

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.