title: PI-88 and novel heparan sulfate mimetics inhibit angiogenesis.
abstract: The heparan sulfate (HS) mimetic PI-88 is a promising inhibitor of tumor growth and metastasis expected to commence phase III clinical evaluation in 2007 as an adjuvant therapy for postresection hepatocellular carcinoma. Its anticancer properties are attributed to inhibition of angiogenesis via antagonism of the interactions of angiogenic growth factors and their receptors with HS. It is also a potent inhibitor of heparanase, an enzyme that plays a key role in both metastasis and angiogenesis. A series of PI-88 analogs have been prepared with enhanced chemical and biological properties. The new compounds consist of single, defined oligosaccharides with specific modifications designed to improve their pharmacokinetic properties. These analogs all 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 inhibitors 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 analogs was also improved, as evidenced primarily by lower clearance in comparison with PI-88. The current data support the development of HS mimetics as potent antiangiogenic anticancer agents.
authors.affiliation: Drug Design Group, Progen, Pharmaceuticals Ltd., Toowong, Queensland 4066, Australia. vito.ferro@progen-pharma.com
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
authors.forename: Keith
authors.initials: K
authors.lastname: Dredge
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.forename: Ian
authors.initials: I
authors.lastname: Bytheway
authors.forename: Caiping
authors.initials: C
authors.lastname: Li
authors.forename: Ken
authors.initials: K
authors.lastname: Johnstone
authors.forename: Tomislav
authors.initials: T
authors.lastname: Karoli
authors.forename: Kat
authors.initials: K
authors.lastname: Davis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Copeman
authors.forename: Anand
authors.initials: A
authors.lastname: Gautam
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019763:Heparin Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006497:Heparan Sulfate / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009844:Oligosaccharides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D019763:Heparin Lyase; D006497:Heparan Sulfate; D009844:Oligosaccharides; D042461:Vascular Endothelial Growth Factor A; C120158:phosphomannopentaose sulfate