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


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.


Paclitaxel Trabectedin Inhibitor LY335979 Mdr1 mRNA Vectorial Transport 
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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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