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The heparan sulfate mimetic PI-88 is an inhibitor of angiogenesis and metastasis that is in clinical development as an anticancer agent and is expected to enter Phase III trials in post-resection hepatocellular carcinoma in 2007. PI-88’s anticancer activities are due to its antagonism of heparan sulfate interactions with angiogenic growth factors and inhibition of heparan sulfate cleavage of basement membranes by heparanase. Analogues of PI-88 with enhanced chemical and biological properties, termed the PG500 series, have been designed and synthesized. Unlike PI-88, which is a mixture of sulfated oligosaccharides, these compounds consist of a single oligosaccharide with various added functionality to improve physicochemical properties. Apart from chemical improvements, these analogues all inhibit heparanase and display strong binding to the pro-angiogenic growth factors FGF1, FGF2 and VEGF similar to PI-88. In human umbilical vein endothelial cell (HUVEC) and dermal human microvascular endothelial cell (dHMVEC) proliferation assays, all compounds potently inhibited FGF2-induced endothelial cell proliferation. However, inhibitory activity against FGF1 or VEGF-induced HUVEC proliferation was compound-specific, i.e. while PI-88 and some PG500 series compounds had poorer activity against these growth factors; others exhibited potent inhibitory activity similar to those generated in the FGF2-induced proliferation assays. Endothelial tube formation using both HUVEC and dHMVEC was potently inhibited by several PG500 series compounds in comparison to PI-88. Two of these compounds were also tested for anti-angiogenic activity in vivo using the AngioSpongeTM and AngioChamberTM assays and were found to significantly reduce blood vessel formation. Moreover, the pharmacokinetic profile of several analogues was also improved, as evidenced primarily by lower clearance in comparison to PI-88. The current data support the development of heparan sulfate mimetics as potent anti-angiogenic compounds and anticancer agents.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA