title: ABT-869, a multitargeted receptor tyrosine kinase inhibitor, reduces tumor microvascularity and improves vascular wall integrity in preclinical tumor models.
abstract: N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N1-(2-fluoro-5-methyl phenyl)-urea (ABT-869) is a novel multitargeted receptor tyrosine kinase inhibitor that demonstrates single-agent activity in preclinical studies and has undergone phase I and II clinical trials. We characterized the mechanism of action of ABT-869 by examining vascular changes after treatment (25 mg/kg per day) in HT1080 fibrosarcoma and SW620 colon carcinoma cells, using immunohistochemistry, dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI), and hypoxic protein detection. We observed the inhibition of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor β phosphorylation in both tumors and changes in tumor vasculature. Reductions in microvessel density and diameter were observed. Vascular-wall integrity was assessed by colocalization of pericytes and basement membrane. Although both microvessel density and total number of pericytes decreased with treatment, the percentage of pericyte coverage on remaining vessels significantly increased. These data suggest the selective ablation of microvessels lacking pericyte coverage. Functional vascular measures DCE-MRI and hypoxia formation were also tested. After 2 days of treatment on the HT1080 model, vascular permeability, K(trans), was reduced by >60% and hypoxic tumor fraction was significantly decreased, which was also seen in the SW620 tumors after 4 days of treatment. Taken together, decreases in vascular permeability and changes in vascular integrity observed in these studies define the mode of action of ABT-869 and may aid in optimizing the timing of therapeutic window for combination therapies.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois 60064-3537, USA. fang.jiang@abbott.com
authors.forename: Fang
authors.initials: F
authors.lastname: Jiang
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Paul
authors.initials: P
authors.lastname: Tapang
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Richard
authors.initials: R
authors.lastname: Lesniewski
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D007191:Indazoles; D010671:Phenylurea Compounds; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases