PI-88 and Novel Heparan Sulfate Mimetics Inhibit Angiogenesis
Autor: | Anaud Gautam, Ligong Liu, Vito Ferro, Kat Davis, Edward Hammond, Elizabeth Copeman, Cai Ping Li, Keith Dredge, Ken D. Johnstone, Ian Bytheway, Tomislav Karoli |
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Rok vydání: | 2007 |
Předmět: |
Vascular Endothelial Growth Factor A
Carcinoma Hepatocellular Angiogenesis Oligosaccharides Fibroblast growth factor chemistry.chemical_compound Biomimetic Materials Animals Humans Heparanase Neoplasm Metastasis Cell Proliferation Tube formation Matrigel Neovascularization Pathologic Endothelial Cells Hematology Heparan sulfate Vascular endothelial growth factor Endothelial stem cell Clinical Trials Phase III as Topic Heparin Lyase Biochemistry chemistry Chemotherapy Adjuvant Cancer research Fibroblast Growth Factor 1 Fibroblast Growth Factor 2 Heparitin Sulfate Cardiology and Cardiovascular Medicine |
Zdroj: | Seminars in Thrombosis and Hemostasis. 33:557-568 |
ISSN: | 1098-9064 0094-6176 |
Popis: | 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. |
Databáze: | OpenAIRE |
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