title: Inhibition of endothelial/smooth muscle cell contact loss by the investigational angiopoietin-2 antibody MEDI3617.
abstract: A tumor's dependence on angiogenesis for survival and growth has led to the advancement of a variety of blood vessel directed anticancer treatment strategies. Overexpression of angiopoietin-2 (Ang-2) in tumor vasculature and its crucial role in angiogenesis, i.e. the destabilization of endothelial/peri-endothelial cell interactions, now raises the possibility of additional novel anti-angiogenic therapeutics. The present study utilized a co-culture sphere model to (i) demonstrate the destabilizing effect of Ang-2 on endothelial/smooth muscle cell contact and (ii) evaluate the impact of the investigational Ang-2 antibody MEDI3617 on endothelial/smooth muscle cell dissociation. Real time imaging of spheres showed both exogenous Ang-2 and PMA induced endogenous Ang-2 secretion resulted in sphere destabilization (loss of endothelial cells from smooth muscle cell core). The presence of MEDI3617 inhibited this process. To assess the anti-angiogenic potential of MEDI3617 in vivo, nude mice were injected intradermally with human renal cell carcinoma cells (Caki-1, Caki-2) and the number of blood vessels induced over a 3 day period was scored. MEDI3617 (2, 10, 20 mg/kg) significantly reduced the initiation of blood vessels for both tumor models at all doses investigated. These data indicate that MEDI3617 treatment significantly impairs the initiation of angiogenesis by inhibiting the Ang-2 mediated disruption of endothelial/muscle cell interaction associated with blood vessel destabilization and thereby reduces tumor cell induced angiogenesis. The results support the notion that targeting the angiopoietin/Tie2 axis may offer novel anti-angiogenic strategies for cancer treatment.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610, USA. nmolnar@ufl.edu
authors.forename: Nikolett
authors.initials: N
authors.lastname: Molnar
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000737:chemistry*; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D009389:Neovascularization, Pathologic
chemical_list: D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C573120:MEDI3617