2.50
Hdl Handle:
http://hdl.handle.net/10541/76283
Title:
Heparin octasaccharides inhibit angiogenesis in vivo.
Authors:
Hasan, Jurjees; Shnyder, Steven D; Clamp, Andrew R; McGown, Alan T; Bicknell, Roy; Presta, Marco; Bibby, Michael; Double, John; Craig, Steven; Leeming, David; Stevenson, Kenneth; Gallagher, John T; Jayson, Gordon C ( 0000-0002-8515-8944 )
Abstract:
BACKGROUND: In previous experiments, we showed that heparin oligosaccharides inhibit the angiogenic cytokine fibroblast growth factor-2. Here, we present the first in vivo study of size-fractionated heparin oligosaccharides in four models of angiogenesis that are progressively less dependent on fibroblast growth factor-2. EXPERIMENTAL DESIGN: Heparin oligosaccharides were prepared using size-exclusion gel filtration chromatography and characterized through depolymerization and strong anion exchange high-performance liquid chromatography. Size-defined oligosaccharides (20 mg/kg/d) were given to mice bearing s.c. sponges that were injected with fibroblast growth factor-2 (100 ng/d). After 14 days, octasaccharides and decasaccharides reduced the microvessel density to levels below control. In a second experiment, HEC-FGF2 human endometrial cancer cells that overexpress fibroblast growth factor-2 were implanted in a hollow fiber placed s.c. in vivo. Oligosaccharides were given at 20 mg/kg/d for 2 weeks and the data again showed that octasaccharides significantly reduced microvessel density around the fiber (P = 0.03). In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors, including vascular endothelial growth factor, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20 mg/kg/d over 3 weeks. Octasaccharides reduced the microvessel density to that of control. Preliminary investigation of 6-O-desulfated heparins showed that these also had antiangiogenic activity. RESULTS: Finally, we examined the inhibitory potential of hexasaccharides and octasaccharides given at 20 mg/kg/d and these inhibited the growth of H460 lung carcinoma in vivo. At clinically attainable concentrations, significant anticoagulation (activated partial thromboplastin time, anti-factor Xa, and anti-factor IIa) was not observed in vitro unless species containing > or =16 saccharide residues were investigated. CONCLUSIONS: Thus, our preclinical data show that heparin octasaccharides represent novel antiangiogenic compounds that can be given without the anticoagulant effects of low molecular weight heparin.
Affiliation:
Cancer Research UK, Department of Medical Oncology, Manchester, UK.
Citation:
Heparin octasaccharides inhibit angiogenesis in vivo. 2005, 11 (22):8172-9 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
15-Nov-2005
URI:
http://hdl.handle.net/10541/76283
DOI:
10.1158/1078-0432.CCR-05-0452
PubMed ID:
16299249
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorHasan, Jurjees-
dc.contributor.authorShnyder, Steven D-
dc.contributor.authorClamp, Andrew R-
dc.contributor.authorMcGown, Alan T-
dc.contributor.authorBicknell, Roy-
dc.contributor.authorPresta, Marco-
dc.contributor.authorBibby, Michael-
dc.contributor.authorDouble, John-
dc.contributor.authorCraig, Steven-
dc.contributor.authorLeeming, David-
dc.contributor.authorStevenson, Kenneth-
dc.contributor.authorGallagher, John T-
dc.contributor.authorJayson, Gordon C-
dc.date.accessioned2009-08-04T17:27:05Z-
dc.date.available2009-08-04T17:27:05Z-
dc.date.issued2005-11-15-
dc.identifier.citationHeparin octasaccharides inhibit angiogenesis in vivo. 2005, 11 (22):8172-9 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid16299249-
dc.identifier.doi10.1158/1078-0432.CCR-05-0452-
dc.identifier.urihttp://hdl.handle.net/10541/76283-
dc.description.abstractBACKGROUND: In previous experiments, we showed that heparin oligosaccharides inhibit the angiogenic cytokine fibroblast growth factor-2. Here, we present the first in vivo study of size-fractionated heparin oligosaccharides in four models of angiogenesis that are progressively less dependent on fibroblast growth factor-2. EXPERIMENTAL DESIGN: Heparin oligosaccharides were prepared using size-exclusion gel filtration chromatography and characterized through depolymerization and strong anion exchange high-performance liquid chromatography. Size-defined oligosaccharides (20 mg/kg/d) were given to mice bearing s.c. sponges that were injected with fibroblast growth factor-2 (100 ng/d). After 14 days, octasaccharides and decasaccharides reduced the microvessel density to levels below control. In a second experiment, HEC-FGF2 human endometrial cancer cells that overexpress fibroblast growth factor-2 were implanted in a hollow fiber placed s.c. in vivo. Oligosaccharides were given at 20 mg/kg/d for 2 weeks and the data again showed that octasaccharides significantly reduced microvessel density around the fiber (P = 0.03). In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors, including vascular endothelial growth factor, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20 mg/kg/d over 3 weeks. Octasaccharides reduced the microvessel density to that of control. Preliminary investigation of 6-O-desulfated heparins showed that these also had antiangiogenic activity. RESULTS: Finally, we examined the inhibitory potential of hexasaccharides and octasaccharides given at 20 mg/kg/d and these inhibited the growth of H460 lung carcinoma in vivo. At clinically attainable concentrations, significant anticoagulation (activated partial thromboplastin time, anti-factor Xa, and anti-factor IIa) was not observed in vitro unless species containing > or =16 saccharide residues were investigated. CONCLUSIONS: Thus, our preclinical data show that heparin octasaccharides represent novel antiangiogenic compounds that can be given without the anticoagulant effects of low molecular weight heparin.en
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subjectLung Canceren
dc.subject.meshAngiogenesis Inhibitors-
dc.subject.meshAnimals-
dc.subject.meshAnticoagulants-
dc.subject.meshCell Line, Tumor-
dc.subject.meshFemale-
dc.subject.meshFibroblast Growth Factor 2-
dc.subject.meshHeparin-
dc.subject.meshHumans-
dc.subject.meshLung Neoplasms-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Nude-
dc.subject.meshNeovascularization, Pathologic-
dc.subject.meshNeovascularization, Physiologic-
dc.subject.meshOligosaccharides-
dc.subject.meshPartial Thromboplastin Time-
dc.subject.meshXenograft Model Antitumor Assays-
dc.titleHeparin octasaccharides inhibit angiogenesis in vivo.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK, Department of Medical Oncology, Manchester, UK.en
dc.identifier.journalClinical Cancer Researchen

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