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.