Oligosaccharides as anti-angiogenic agents

Abstract

Background: Several studies of drugs that inhibit tumour angiogenesis have shown improvements in the survival of cancer patients, thus validating angiogenesis as a clinically relevant target. Both intracellular and extracellular approaches have shown promising results in clinical situations. Objectives: To compare and contrast oligosaccharide therapies and other anti-angiogenic compounds for their benefits and toxicity. Methods: Analysis of the relevant literature including presentations at recent conferences. Results: Receptor tyrosine kinase inhibitors are orally available but have a broad spectrum of activity which is associated with toxicity. Antibodies are associated with different toxicities, however, they are administered parenterally. Oligosaccharides that act as competitive inhibitors of heparan sulfate (HS) are in the early and late phases of clinical development. The advantage of oligosaccharides should be that they can be designed to target several angiogenic molecules, that they are relatively safe and that they can be administered subcutaneously at home. The key questions concerning their development focus on whether compounds with sufficient affinity and relative specificity can be generated, whether they are active at doses that do not perturb the coagulation cascade to a clinically dangerous level, whether the synthetic routes are scalable and, whether the current Phase III trials will yield positive results. Conclusions: Saccharides represent a novel and exciting therapeutic approach that targets a spectrum of angiogenic molecules that cannot be inhibited through established drug development programmes.

Keywords::

• angiogenesis
• bevacizumab
• FGF2
• fibroblast growth factor-2
• heparan sulfate
• heparin
• HS
• LMWH
• low molecular weight heparin
• pentosan polysulfate
• phosphomannopentaose
• PI-88
• PPS
• tyrosine kinase inhibitors
• VEGF
• VEGF-trap