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Investigational New Drugs

, 25:1 | Cite as

Trabectedin (ET-743, Yondelis™) is a substrate for P-glycoprotein, but only high expression of P-glycoprotein confers the multidrug resistance phenotype

  • Jan-Hendrik Beumer
  • Tessa Buckle
  • Mariet Ouwehand
  • Niels E. F. Franke
  • Luis Lopez-Lazaro
  • Jan H. M. Schellens
  • Jos H. Beijnen
  • Olaf van TellingenEmail author
Article

Summary

Trabectedin (ET-743, Yondelis™) is a novel anticancer drug currently undergoing phase II and III investigations. There are various and conflicting reports whether trabectedin is a substrate for P-glycoprotein (P-gp), an important factor in drug disposition and multi-drug resistance (MDR). We have now unambiguously shown that trabectedin is a P-gp substrate by investigating vectorial transport over monolayers of LLC-PK1 pig kidney and Madine-Darby Canine kidney (MDCK) cells and the mdr1a and/or MDR1 transfected subclones. We further characterized the cytotoxic effects and cellular accumulation of trabectedin in these cell lines as well as in a panel of other cell lines with high or moderate expression levels of P-gp. Trabectedin displayed the typical MDR phenotype only in highly P-gp expressing cell lines, but not in cell lines with expression levels more closely conforming to clinical samples, suggesting that P-gp will not confer resistance to trabectedin in cancer patients.

Keywords

Paclitaxel Trabectedin Inhibitor LY335979 Mdr1 mRNA Vectorial Transport 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Jan-Hendrik Beumer
    • 1
  • Tessa Buckle
    • 2
  • Mariet Ouwehand
    • 2
  • Niels E. F. Franke
    • 2
  • Luis Lopez-Lazaro
    • 3
  • Jan H. M. Schellens
    • 4
    • 5
  • Jos H. Beijnen
    • 1
    • 5
  • Olaf van Tellingen
    • 2
    • 6
    Email author
  1. 1.Department of Pharmacy & PharmacologyThe Netherlands Cancer Institute/Slotervaart HospitalAmsterdamThe Netherlands
  2. 2.Department of Clinical ChemistryThe Netherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  3. 3.PharmaMar, Clinical PharmacologyColmenar ViejoMadridSpain
  4. 4.Department of Medical OncologyThe Netherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  5. 5.Department of Biomedical Analysis, Division of Drug Toxicology, Faculty of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  6. 6.Netherlands Cancer InstituteAmsterdamThe Netherlands

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