ABT-869 is a novel multi-targeted 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 following treatment (25/mg/kg/day) in the HT1080 fibrosarcoma and SW620 colon carcinoma, using immunohistochemistry, DCE-MRI and hypoxic protein detection. We observed inhibition of VEGFR-2 and PDGFR-beta 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, 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 Ktrans was reduced by >60% and hypoxic tumor fraction was significant decreased, as well as 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.
- Preclinical tumor models
- Receptor tyrosine kinase inhibitor
- Tumor vasculature
- Vascular wall integrity
- Received December 15, 2010.
- Revision received April 18, 2011.
- Accepted April 19, 2011.
- The American Society for Pharmacology and Experimental Therapeutics