ABSTRACT
PURPOSE: We investigated the ability of the combinatorial administration of different inhibitors with activities on glioma angiogenesis, migration, and proliferation to produce a prolonged inhibition of glioma growth. EXPERIMENTAL DESIGN: We combined inhibitors affecting solely tumor angiogenesis (PF-4/CTF, cyclo-VEGI) or inhibitors affecting both angiogenesis and invasion together (PEX, PF-4/DLR). RESULTS: When administered in combination, these drugs produced a prolonged and increased inhibition of glioma growth independently from the type of inhibitor used. The combinatory administration was more effective than the administration of a single inhibitor alone, and a strong therapeutic response was reached with a significantly lower amount of protein. The strongest inhibition was observed when human PEX and PF-4/DLR, which affect both glioma angiogenesis and invasion by separate mechanisms, were combined. CONCLUSIONS: This supports the concept that prolonged glioma growth inhibition can be achieved by simultaneous delivery of molecules that target both tumor and endothelial cells and acting by separate mechanisms.
Subject(s)
Brain Neoplasms/drug therapy , Glioma/drug therapy , Neovascularization, Pathologic , Animals , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Collagen , Disease Models, Animal , Drug Combinations , Endothelial Growth Factors/biosynthesis , Endothelium, Vascular/pathology , Glioma/pathology , Humans , Laminin , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microcirculation , Microscopy, Fluorescence , Neoplasm Invasiveness , Neoplasm Transplantation , Neoplasms/pathology , PHEX Phosphate Regulating Neutral Endopeptidase , Peptides, Cyclic/biosynthesis , Platelet Factor 4/biosynthesis , Proteins/metabolism , Proteoglycans , Recombinant Proteins/chemistry , Time FactorsABSTRACT
Blocking angiogenesis is an attractive strategy to inhibit tumor growth, invasion, and metastasis. We describe here the structure and the biological action of a new cyclic peptide derived from vascular endothelial growth factor (VEGF). This 17-amino acid molecule designated cyclopeptidic vascular endothelial growth inhibitor (cyclo-VEGI, CBO-P11) encompasses residues 79-93 of VEGF which are involved in the interaction with VEGF receptor-2. In aqueous solution, cyclo-VEGI presents a propensity to adopt a helix conformation that was largely unexpected because only beta-sheet structures or random coil conformations have been observed for macrocyclic peptides. Cyclo-VEGI inhibits binding of iodinated VEGF165 to endothelial cells, endothelial cells proliferation, migration, and signaling induced by VEGF165. This peptide also exhibits anti-angiogenic activity in vivo on the differentiated chicken chorioallantoic membrane. Furthermore, cyclo-VEGI significantly blocks the growth of established intracranial glioma in nude and syngeneic mice and improves survival without side effects. Taken together, these results suggest that cyclo-VEGI is an attractive candidate for the development of novel angiogenesis inhibitor molecules useful for the treatment of cancer and other angiogenesis-related diseases.
