Effect of the Multitargeted Receptor Tyrosine Kinase Inhibitor, ABT-869 [N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea], on Blood Pressure in Conscious Rats and Mice: Reversal with Antihypertensive Agents and Effect on Tumor Growth Inhibition

  1. Pamela H. Franklin,
  2. Patricia N. Banfor,
  3. Paul Tapang,
  4. Jason A. Segreti,
  5. Deborah L. Widomski,
  6. Kelly J. Larson,
  7. William T. Noonan,
  8. Gary A. Gintant,
  9. Steven K. Davidsen,
  10. Daniel H. Albert,
  11. Ryan M. Fryer and
  12. Bryan F. Cox
  1. Integrative Pharmacology (P.H.F., P.N.B., J.A.S., D.L.W., K.J.L., W.T.N., G.A.G., R.M.F., B.F.C.) and Cancer Research (P.T., S.K.D., D.H.A.), Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
  1. Address correspondence to:
    Bryan F. Cox, Department of Integrative Pharmacology, R46R, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119. E-mail: bryan.f.cox{at}abbott.com

Abstract

ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea] is a novel multitargeted inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase family members. ABT-869 demonstrates tumor growth inhibition in multiple preclinical animal models and in early clinical trials. VEGF receptor inhibition is also associated with reversible hypertension that may limit its benefit clinically. To evaluate optimal therapeutic approaches to prevent hypertension with VEGF receptor inhibition, we characterized the dose-dependent effects of seven antihypertensive agents from three mechanistic classes [angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs)] on hypertension induced by ABT-869 in conscious telemetry rats. We report that ABT-869-induced hypertension can be prevented and reversed with subtherapeutic or therapeutic doses of antihypertensive drugs with a general rank order of ACEi > ARB > CCB. In SCID mice, the ACE inhibitor, enalapril (C20H28N2O5·C4H4O4) at 30 mg/kg, prevented hypertension, with no attenuation of the antitumor efficacy of ABT-869. These studies demonstrate that the adverse cardiovascular effects of the VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, are readily controlled by conventional antihypertensive therapy without affecting antitumor efficacy.

Footnotes

  • P.H.F. and P.N.B. contributed equally to this work.

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

  • doi:10.1124/jpet.108.144816.

  • ABBREVIATIONS: RTK, receptor tyrosine kinase; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; ABT-869, N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea; PDGF, platelet-derived growth factor; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; MAP, mean arterial pressure; AUC, area(s) under the curve; ANOVA, analysis of variance; enalapril, C20H28N2O5·C4H4O4; lisinopril, C21H31N3O5·2H2O; ramipril, C23H32N2O5; telmisartan, C33H30N4O2; eprosartan, C23H24N2O4S·CH4O3S; nifedipine, C17H18N2O6; amlodipine, C20H25CIN2O5·C6H6O3S.

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received August 27, 2008.
    • Accepted February 27, 2009.

Responses to this article

    • Stephen R. Wedge and
    • Jon O. Curwen
    Management of hypertension induced by VEGF signalling inhibition JPET published online November 6, 2009
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  1. Published online before print March 2, 2009, doi: 10.1124/jpet.108.144816 JPET June 2009 vol. 329 no. 3 928-937
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