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Research ArticleDrug Discovery and Translational Medicine

ABT-869, a Multitargeted Receptor Tyrosine Kinase Inhibitor, Reduces Tumor Microvascularity and Improves Vascular Wall Integrity in Preclinical Tumor Models

Fang Jiang, Daniel H. Albert, Yanping Luo, Paul Tapang, Ke Zhang, Steven K. Davidsen, Gerard B. Fox, Richard Lesniewski and Evelyn M. McKeegan
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 134-142; DOI: https://doi.org/10.1124/jpet.110.178061
Fang Jiang
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Daniel H. Albert
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Yanping Luo
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Paul Tapang
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Ke Zhang
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Steven K. Davidsen
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Gerard B. Fox
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Richard Lesniewski
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Evelyn M. McKeegan
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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, Ktrans, 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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.178061.

  • ABBREVIATIONS:

    RTK
    receptor tyrosine kinase
    PDGF
    platelet-derived growth factor
    PDGFR
    PDGF receptor
    pPDGFR
    phospho-PDGFR
    VEGF
    vascular endothelial growth factor
    VEGFR
    VEGF receptor
    pVEGFR
    phospho-VEGFR
    MV
    microvessels
    DCE-MRI
    dynamic contrast enhanced-magnetic resonance imaging
    ABT-869
    N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N1-(2-fluoro-5-methylphenyl)-urea
    PBS
    phosphate-buffered saline
    DAPI
    4′,6-diamidino-2-phenylindole
    FITC
    fluorescein isothiocyanate
    SMA
    smooth muscle actin
    IHC
    immunohistochemistry
    vWF
    von Willebrand factor
    Gd-DTPA
    gadopentetate dimeglumine-diethylene triamine pentaacetic acid.

  • Received December 15, 2010.
  • Accepted April 19, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleDrug Discovery and Translational Medicine

ABT-869, a Multitargeted Receptor Tyrosine Kinase Inhibitor, Reduces Tumor Microvascularity and Improves Vascular Wall Integrity in Preclinical Tumor Models

Fang Jiang, Daniel H. Albert, Yanping Luo, Paul Tapang, Ke Zhang, Steven K. Davidsen, Gerard B. Fox, Richard Lesniewski and Evelyn M. McKeegan
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 134-142; DOI: https://doi.org/10.1124/jpet.110.178061

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Research ArticleDrug Discovery and Translational Medicine

ABT-869, a Multitargeted Receptor Tyrosine Kinase Inhibitor, Reduces Tumor Microvascularity and Improves Vascular Wall Integrity in Preclinical Tumor Models

Fang Jiang, Daniel H. Albert, Yanping Luo, Paul Tapang, Ke Zhang, Steven K. Davidsen, Gerard B. Fox, Richard Lesniewski and Evelyn M. McKeegan
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 134-142; DOI: https://doi.org/10.1124/jpet.110.178061
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