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

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • 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

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Experimental and Molecular Therapeutics 25: Mechanisms of Drug Resistance and Reversal

Imatinib-induced upregulation of ABCG2 (BCRP) and ABCB1 (MDR1) may represent a novel mechanism of pharmacokinetic drug resistance in cancer patients chronically treated with imatinib

Herman Burger, Hans Van Tol, Mariel Brok, Erik A. C. Wiemer, Ernst A. De Bruin, Gunther Guetens, Alex Sparreboom and Kees Nooter
Herman Burger
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hans Van Tol
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mariel Brok
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Erik A. C. Wiemer
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ernst A. De Bruin
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gunther Guetens
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alex Sparreboom
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kees Nooter
Erasmus MC / Josephine Nefkens Institute, Rotterdam, The Netherlands, Erasmus MC, Rotterdam, The Netherlands, Laboratory Experimental Oncology, KU Leuven / UZ Gasthuisberg, Leuven, Belgium, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI:  Published May 2005
  • Article
  • Info & Metrics
Loading
Proc Amer Assoc Cancer Res, Volume 46, 2005

Abstract

2639

Imatinib mesylate (Gleevec) shows selective inhibition of the tyrosine kinase activity of the BCR-ABL fusion protein and of the receptors for the stem cell factor (c-KIT) and platelet-derived growth factor. This archetype of a targeted drug is successfully used in the treatment of Ph+ chronic and acute leukemias, and gastrointestinal stromal tumors. Since imatinib is taken orally on a daily basis, it is conceivable that this chronic administration may eventually lead to development of cellular resistance and subsequent treatment failure. Indeed, the vast majority of patients progress while on therapy and several imatinib resistance mechanisms have been documented. Gene amplification or somatic mutations in the drug’s target genes are generally thought to be responsible for this acquired unresponsiveness. We investigated whether ABC drug pumps are also implicated in imatinib resistance. First we examined whether imatinib is a substrate for the ABCG2 drug pump. Using a panel of well-defined ABCG2-overexpressing cell lines we demonstrated that imatinib is indeed a substrate for ABCG2, that it competes with mitoxantrone for drug export, and that ABCG2-mediated efflux can be reversed by the fumitremorgin C analog Ko-143. Furthermore, ABCB1-mediated outward transport of imatinib was demonstrated in drug uptake experiments using C14 labeled imatinib, in line with previous reports. Evidently, imatinib is a substrate for both ABCG2 and ABCB1. Since both drug pumps are highly expressed in the gastrointestinal tract, they might not only play a role in cellular resistance of tumor cells but also influence the gastrointestinal absorption of imatinib. So next, we investigated whether chronic oral administration of imatinib might lead to the induction of intestinal transport proteins such as ABCB1, ABCG2, ABCC1 and ABCC2 (MRP1/2). Using Caco-2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure to imatinib (10 μM) specifically upregulates the expression of ABCG2 and ABCB1. The drug-induced gene activation was not mediated by the human orphan nuclear receptor SXR. Importantly, long-term exposure of Caco-2 cells to imatinib resulted in a decreased intracellular accumulation (∼50%) due to enhanced ABCG2- and ABCB1-mediated efflux. It might be anticipated that drug-induced upregulation of these intestinal pumps reduce the oral bioavailability of imatinib, and thereby represent a mechanism of acquired pharmacokinetic drug resistance in cancer patients chronically treated with imatinib. So, our own in vitro findings and several in vivo observations provide evidence that pharmacokinetic resistance may also play a definitive role in the ultimate resistance of patients on chronic imatinib. The latter may have serious implications for the chronic imatinib treatment of cancer patients.

  • American Association for Cancer Research
Previous
Back to top
Cancer Research: 65 (9 Supplement)
May 2005
Volume 65, Issue 9 Supplement
  • Table of Contents
  • Index by Author

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research 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.
Imatinib-induced upregulation of ABCG2 (BCRP) and ABCB1 (MDR1) may represent a novel mechanism of pharmacokinetic drug resistance in cancer patients chronically treated with imatinib
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Imatinib-induced upregulation of ABCG2 (BCRP) and ABCB1 (MDR1) may represent a novel mechanism of pharmacokinetic drug resistance in cancer patients chronically treated with imatinib
Herman Burger, Hans Van Tol, Mariel Brok, Erik A. C. Wiemer, Ernst A. De Bruin, Gunther Guetens, Alex Sparreboom and Kees Nooter
Cancer Res May 1 2005 (65) (9 Supplement) 621;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Imatinib-induced upregulation of ABCG2 (BCRP) and ABCB1 (MDR1) may represent a novel mechanism of pharmacokinetic drug resistance in cancer patients chronically treated with imatinib
Herman Burger, Hans Van Tol, Mariel Brok, Erik A. C. Wiemer, Ernst A. De Bruin, Gunther Guetens, Alex Sparreboom and Kees Nooter
Cancer Res May 1 2005 (65) (9 Supplement) 621;
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
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Major vault protein contributes to intrinsic drug resistance in cancer cells due to its role in lysosomal integrity
  • Characterization of HER2 overexpressing breast cell lines selected for long-term culture with trastuzumab
  • A pharmacogenomic analysis reveals increased sensitivity of MDR1/P-glycoprotein-overexpressing cancer cells to thiosemicarbazone-derivatives
Show more Experimental and Molecular Therapeutics 25: Mechanisms of Drug Resistance and Reversal
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

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

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

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

Copyright © 2018 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement