The structure and function of antiangiogenic oligosaccharides
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
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Technical Summary
Angiogenesis, the formation of new blood vessels, has been validated in several randomised trials as a target for anti-cancer treatment. Drugs that inhibit Vascular Endothelial Growth Factor (VEGF) augment the benefits of cytotoxic chemotherapy and improve the median survival of patients with solid tumours. However, the long term survival from advanced cancer has improved to a lesser extent and we need to increase the benefit associated with this new class of drugs by inhibiting additional angiogenic cytokines.
Several angiogenic growth factors are dependent on cell surface heparan sulfate (HS) for their
biological activity. We have shown that heparin octasaccharides inhibit angiogenesis in vitro and in vivo and this is mediated through the competitive inhibition of heparan sulfate-mediated activation of FGF2. Our synthesis programme has developed the first scalable and inexpensive method to generate large amounts of the key iduronate unit and application to heparin octasaccharides has enabled larger scale provision of these saccharides which have anti-angiogenic activity. We therefore propose to generate, characterise and investigate several families of heparan sulfate based saccharides with respect to their ability to inhibit the angiogenic cytokines FGF2 and VEGF165,189,202 (the HS-dependent isoforms of VEGF):
HS octasaccharides: We will generate a range of site-specifically sulfated octasaccharides to
establish the most critical sulfate groups on the saccharide backbone that determine FGF2 and
VEGF activity.
Anionically substituted octasaccharides will be made that incorporate different anionic
substitutions at sites identified as being critical through the HS octasaccharides set of molecules
(above).
Dimerised octasaccharides: We will evaluate the impact of dimerised oligosaccharides using
parallel or anti-parallel linkers and also investigate the impact of increasing the linker chain length on FGF2 and VEGF activity in vitro and in vivo. This strategy will provide a platform technology to address the synthesis of an array of spacer-variable heparin systems to probe for multi-target effects.
This innovative approach will generate several types of completely novel molecules that will
establish our team as the UK glycotherapeutics unit, enhanced by the key synergy between design and synthesis of specific novel heparin-based targets allied to a leading international facility in heparin/cancer biology; a programme that will lead directly to further testing in the oncology clinic.
Several angiogenic growth factors are dependent on cell surface heparan sulfate (HS) for their
biological activity. We have shown that heparin octasaccharides inhibit angiogenesis in vitro and in vivo and this is mediated through the competitive inhibition of heparan sulfate-mediated activation of FGF2. Our synthesis programme has developed the first scalable and inexpensive method to generate large amounts of the key iduronate unit and application to heparin octasaccharides has enabled larger scale provision of these saccharides which have anti-angiogenic activity. We therefore propose to generate, characterise and investigate several families of heparan sulfate based saccharides with respect to their ability to inhibit the angiogenic cytokines FGF2 and VEGF165,189,202 (the HS-dependent isoforms of VEGF):
HS octasaccharides: We will generate a range of site-specifically sulfated octasaccharides to
establish the most critical sulfate groups on the saccharide backbone that determine FGF2 and
VEGF activity.
Anionically substituted octasaccharides will be made that incorporate different anionic
substitutions at sites identified as being critical through the HS octasaccharides set of molecules
(above).
Dimerised octasaccharides: We will evaluate the impact of dimerised oligosaccharides using
parallel or anti-parallel linkers and also investigate the impact of increasing the linker chain length on FGF2 and VEGF activity in vitro and in vivo. This strategy will provide a platform technology to address the synthesis of an array of spacer-variable heparin systems to probe for multi-target effects.
This innovative approach will generate several types of completely novel molecules that will
establish our team as the UK glycotherapeutics unit, enhanced by the key synergy between design and synthesis of specific novel heparin-based targets allied to a leading international facility in heparin/cancer biology; a programme that will lead directly to further testing in the oncology clinic.
