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Title: Heparin oligosaccharides inhibit angiogenesis in vivo
Author: Hasan, Jurjees
ISNI:       0000 0001 3543 5766
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2007
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The prototypic heparan sulfate (HS)-dependent angiogenic cytokine is FGF-2. Here we present the first in vivo study of size fractionated heparin oligosaccharides in 3 models of angiogenesis that are progressively less dependent on FGF-2. We developed the modified hollow fibre assay, a novel model for quantifying angiogenesis in vivo. We tested the ability of size defined oligosaccharides (dp 6-14) to inhibit FGF-2 in a sponge model of angiogenesis, where the process can be driven by a defined angiogenic molecule. Sponges were implanted subcutaneously and injected with FGF2 100 ng/day and oligosaccharides (20 mglkg/day). After 14 days the sponges were excised and the microvessel density (MVD) measured. Octasaccharides were the most potent species, reducing MVD to levels below those observed in saline treated implants. In a second experiment HEC-FGF2 human endometrial cancer cells that over-express FGF-2 were implanted in a hollow fibre placed subcutaneously in vivo. Oligosaccharides were administered at 20 mglkg/day for 2 weeks and the data again showed that octasaccharides significantly reduced MVD around the fiber. In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors including VEGF, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20mglkg/day over three weeks. The data showed that octasaccharides were able to reduce the microvessel density to the level of angiogenesis present in empty hollow fibres. Preliminary investigation of 6-0-desulfated heparins showed that these also had anti-angiogenic activity. In summary, we have shown that heparin octasaccharides have antiangiogenic activity in vivo in several models of variable dependence on FGF-2. We have now embarked on a synthetic programme to produce and investigate oligosaccharides with predefined sulfation patterns and cytokine specificities as FGF inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available