title: Murine colitis treated with multitargeted tyrosine kinase inhibitors.
abstract: BACKGROUND
  Angiogenesis, a known pathogenic component of neoplastic and nonneoplastic diseases, serves as a therapeutic target. Vascular endothelial growth factor (VEGF) and angiogenesis are clinically elevated in inflammatory bowel disease. By targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with receptor tyrosine kinase inhibitors in a murine model of colitis, we hypothesize that angiogenesis will be suppressed and disease severity improved.
  
  
  METHODS
  Sorafenib, sunitinib, and axitinib were administered by oral gavage in a murine model of dextran sodium sulfate (DSS) colitis. Inflammation score, microvessel density (MVD), and gene expression of VEGF, VEGFR, platelet-derived growth factor, PDGFR, Ang-2, and epidermal growth factor receptor was assessed.
  
  
  RESULTS
  Inflammation and MVD were elevated in groups receiving DSS, but were similar between DSS-only and treatment cohorts. Unexpected weight loss was present in the gavaged groups versus DSS only. In treated groups, VEGFR was significantly decreased (P = 0.002) and VEGF gene expression trended down (P = 0.213) versus DSS only. Neither the platelet-derived growth factor/PDGFR pathway nor the alternative pathways, Ang-2 and epidermal growth factor receptor, were significantly changed from DSS control in treatment cohorts.
  
  
  CONCLUSIONS
  This study confirms the association between inflammation and MVD. Antiangiogenic receptor tyrosine kinase inhibitors suppressed the VEGF/VEGFR pathway but the expected decrease in colonic MVD did not follow, suggesting possible involvement of other angiogenic pathway(s). In the DSS model of colitis, vehicle selection and mouse strain can impact disease response.
authors.affiliation: Peña Colorectal Center, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jennifer Leslie
authors.initials: JL
authors.lastname: Knod
authors.affiliation: Peña Colorectal Center, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kelly
authors.initials: K
authors.lastname: Crawford
authors.affiliation: Peña Colorectal Center, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Mary
authors.initials: M
authors.lastname: Dusing
authors.affiliation: Peña Colorectal Center, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Jason.Frischer@cchmc.org.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
mesh_terms: D000818:Animals; D000077784:Axitinib; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib; D000077210:Sunitinib
keywords: Angiogenesis; Colitis; Inflammatory bowel disease; Receptor tyrosine kinase inhibitors; VEGF