Skip to main content
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Research Articles: Therapeutics

Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor

Daniel H. Albert, Paul Tapang, Terrance J. Magoc, Lori J. Pease, David R. Reuter, Ru-Qi Wei, Junling Li, Jun Guo, Peter F. Bousquet, Nayereh S. Ghoreishi-Haack, Baole Wang, Gail T. Bukofzer, Yi-Chun Wang, Jason A. Stavropoulos, Kresna Hartandi, Amanda L. Niquette, Nirupama Soni, Eric F. Johnson, J. Owen McCall, Jennifer J. Bouska, Yanping Luo, Cherrie K. Donawho, Yujia Dai, Patrick A. Marcotte, Keith B. Glaser, Michael R. Michaelides and Steven K. Davidsen
Daniel H. Albert
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Tapang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terrance J. Magoc
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lori J. Pease
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David R. Reuter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ru-Qi Wei
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Junling Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jun Guo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter F. Bousquet
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nayereh S. Ghoreishi-Haack
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Baole Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gail T. Bukofzer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yi-Chun Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jason A. Stavropoulos
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kresna Hartandi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amanda L. Niquette
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nirupama Soni
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric F. Johnson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Owen McCall
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jennifer J. Bouska
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yanping Luo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cherrie K. Donawho
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yujia Dai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrick A. Marcotte
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keith B. Glaser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael R. Michaelides
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven K. Davidsen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1535-7163.MCT-05-0410 Published April 2006
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 μmol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-β, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5–5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 μg/mL, ≥7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer. [Mol Cancer Ther 2006;5(4):995–1006]

Keywords:
  • Receptor tyrosine kinase inhibitor (RTKI)
  • KDR
  • FLT1
  • FLT4
  • VEGF
  • VEGFR-2
  • VEGFR-1
  • VEGFR-3
  • xenografts
  • AML

Footnotes

  • ↵1 J. Li et al. ABT-869 a multi-targeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Cancer Res, submitted for publication.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 21, 2006.
    • Received October 7, 2005.
    • Revision received January 30, 2006.
  • American Association for Cancer Research
View Full Text
PreviousNext
Back to top
Molecular Cancer Therapeutics: 5 (4)
April 2006
Volume 5, Issue 4
  • Table of Contents
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor
Daniel H. Albert, Paul Tapang, Terrance J. Magoc, Lori J. Pease, David R. Reuter, Ru-Qi Wei, Junling Li, Jun Guo, Peter F. Bousquet, Nayereh S. Ghoreishi-Haack, Baole Wang, Gail T. Bukofzer, Yi-Chun Wang, Jason A. Stavropoulos, Kresna Hartandi, Amanda L. Niquette, Nirupama Soni, Eric F. Johnson, J. Owen McCall, Jennifer J. Bouska, Yanping Luo, Cherrie K. Donawho, Yujia Dai, Patrick A. Marcotte, Keith B. Glaser, Michael R. Michaelides and Steven K. Davidsen
Mol Cancer Ther April 1 2006 (5) (4) 995-1006; DOI: 10.1158/1535-7163.MCT-05-0410

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor
Daniel H. Albert, Paul Tapang, Terrance J. Magoc, Lori J. Pease, David R. Reuter, Ru-Qi Wei, Junling Li, Jun Guo, Peter F. Bousquet, Nayereh S. Ghoreishi-Haack, Baole Wang, Gail T. Bukofzer, Yi-Chun Wang, Jason A. Stavropoulos, Kresna Hartandi, Amanda L. Niquette, Nirupama Soni, Eric F. Johnson, J. Owen McCall, Jennifer J. Bouska, Yanping Luo, Cherrie K. Donawho, Yujia Dai, Patrick A. Marcotte, Keith B. Glaser, Michael R. Michaelides and Steven K. Davidsen
Mol Cancer Ther April 1 2006 (5) (4) 995-1006; DOI: 10.1158/1535-7163.MCT-05-0410
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton
  • MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death
  • Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice
Show more Research Articles: Therapeutics
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About MCT

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement