PI-88 and novel heparan sulfate mimetics inhibit angiogenesis

Ferro, Vito, Dredge, Keith, Liu, Ligong, Hammond, Edward, Bytheway, Ian, Li, Caiping, Johnstone, Ken, Karoli, Tomislav, Davis, Kat, Copeman, Elizabeth and Gautam, Anand: (2007) PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Seminars in Thrombosis and Hemostasis, 33 5: 557-562. doi:10.1055/s-2007-982088


Author Ferro, Vito
Dredge, Keith
Liu, Ligong
Hammond, Edward
Bytheway, Ian
Li, Caiping
Johnstone, Ken
Karoli, Tomislav
Davis, Kat
Copeman, Elizabeth
Gautam, Anand:
Title PI-88 and novel heparan sulfate mimetics inhibit angiogenesis
Journal name Seminars in Thrombosis and Hemostasis   Check publisher's open access policy
ISSN 0094-6176
Publication date 2007-07
Sub-type Article (original research)
DOI 10.1055/s-2007-982088
Volume 33
Issue 5
Start page 557
End page 562
Total pages 6
Place of publication New York
Publisher Thieme
Language eng
Subject 030401 Biologically Active Molecules
030503 Organic Chemical Synthesis
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. KEYWORDS
Keyword PI-88
heparan sulfate mimetics
heparanase inhibitors
angiogenesis inhibitors
sulfated oligosaccharides
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 84 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 92 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 02 Feb 2009, 14:33:33 EST by Maryanne Watson on behalf of Institute for Molecular Bioscience