PI-88 and novel heparan sulfate mimetics inhibit angiogenesis.
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.
Ferro
Vito
V
Drug Design Group, Progen, Pharmaceuticals Ltd., Toowong, Queensland 4066, Australia. vito.ferro@progen-pharma.com
Dredge
Keith
K
Liu
Ligong
L
Hammond
Edward
E
Bytheway
Ian
I
Li
Caiping
C
Johnstone
Ken
K
Karoli
Tomislav
T
Davis
Kat
K
Copeman
Elizabeth
E
Gautam
Anand
A
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
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