【摘要】 已有的研究表明,肝素可以作为P-选择素的配体,显著抑制肿瘤转移过程中P-选择素介导的肿瘤细胞与血小板间的粘附.但是,肝素被P-选择素识别所必需的确切寡糖结构信息仍很缺乏.通过选择性化学修饰方法制备了2种低抗凝血肝素衍生物,即羧基还原肝素(CR-肝素)和羧基还原后再硫酸化肝素(SCR-肝素),系统地研究了它们对P-选择素介导的A375细胞粘附的抑制.研究结果表明,显著失去抗凝血活性的CR-肝素仍能有效地抑制P-选择素介导的A375细胞粘附,说明肝素的C6羧基并不是被P-选择素识别所必需的.而SCR-肝素所发生的C6羧基向羟甲硫酸酯基的转化却显著降低了抗粘附活性,说明P-选择素对肝素的识别并不只依赖于肝素的电荷密度.研究结果为深入阐明拮抗P-选择素介导的肿瘤细胞粘附的分子机制提供了有价值的实验基础.更多还原

【Abstract】 Several studies have demonstrated that heparin can significantly inhibit the P-selectin-mediated interaction of platelets and tumor cells during metastasis as a P-selectin ligand. However, little information is available about the specific oligosaccharide structures of heparin in recognition by P-selectin. Two chemically modified heparins, CR-heparin and SCR-heparin were prepared, to explore if such heparin derivatives can reduce the P-selectin-mediated A375 tumor cell adhesion. The results indicated that CR-heparin with low anticoagulant activity could significantly inhibit the P-selectin-mediated A375 tumor cell adhesion, demonstrating that 6-carboxyl group of the glucuronic acid in heparin may not be crucial for recognizing by P-selectin. In contrast, SCR-heparin reduced the inhibiting activity dramatically, suggesting that the recognition of P-selectin to heparin depend on not only densities of negative charge. These results provide valuable experimental evidence for clarifying the molecular mechanism of P-selectin-mediated tumor cell adhesion.更多还原