新型抗肿瘤药PI-88及其类似物

硫酸乙酰肝素类似物PI-88是一种有前景的肿瘤生长及转移抑制剂，可作为肝癌切除手术后的辅助治疗，通过抑制血管生长而产生抗肿瘤作用。同时它也是一种强效的乙酰肝素酶抑制剂，乙酰肝素酶是一种在肿瘤转移以及血管生长过程中起关键作用的酶。已经合成一系列PI-88类似物，这些类似物都可抑制乙酰肝素酶，与成纤维细胞生长因子（FGF）-1，FGF-2，血管内皮生长因子的亲和力和PI-88类似。与PI-88相比，有些新化合物显示出更强的抑制生长因子诱导的内皮细胞增殖及内皮细胞管道生成的作用，体内试验也证实有明显的抑制血管生成的作用。此外，部分新化合物药代动力学性质也得到改善。PI-88及其类似物作为一类有效抑制血管生长的抗肿瘤药物的研究正在进行中

Novel anticancer agents: PI-88 and its mimetics

The heparan sulfate(HS) mimetic PI-88 is a promising inhibitor of tumor growth and metastasis as an adjuvant therapy for postresection hepatocellular carcinoma. Its anti-neoplastic effect is mediated through the inhibition of tumor angiogenesis. It is also a potent inhibitor of heparanase,an enzyme that plays a key role in both tumor metastasis and angiogenesis.A series of PI-88 analogues have been synthesized, which can inhibit heparanase and bind to the angiogenic fibroblast growth factor 1(FGF-1),FGF-2,and vascular endothelial growth factor with similar affinity to PI-88. However,compared with PI-88,some of the newly designed compounds are more potent inhibitos of growth factor-induced endothelial cell proliferation and of endothelial tube formation on matrigel. Representative compounds were also tested for antiangiogenic activity in vivo and were found to reduce significantly blood vessel formation. Moreover,the pharmacokinetic profile of several analogues was also improved. The current data support the development of PI-88 mimetics as potent antiangiogenic anticancer agents.