Cancer Chemotherapy and Pharmacology

, Volume 53, Issue 5, pp 363–369

Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023

  • Hans Minderman
  • Tracy A. Brooks
  • Kieran L. O’Loughlin
  • Iwao Ojima
  • Ralph J. Bernacki
  • Maria R. Baer
Original Article



The taxanes paclitaxel and docetaxel are substrates for P-glycoprotein (Pgp), an ATP-binding cassette (ABC) transport protein associated with multidrug resistance (MDR). In contrast, the synthetic taxane ortataxel (BAY 59-8862, IDN-5109) is effective against Pgp-expressing cells by virtue of modulation of Pgp-mediated transport. The synthetic taxane tRA96023 also modulates Pgp and is noncytotoxic due to removal of the tubulin-binding side chain at the C-13 position of the taxane backbone. We studied the effects of ortataxel and tRA96023 on the other MDR-associated ABC transport proteins, multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP, MXR, ABCG2).


Modulation of mitoxantrone, daunorubicin and doxorubicin retention and cytotoxicity by ortataxel and tRA96023 was studied in established cell lines overexpressing Pgp, MRP-1 and wild type (BCRPR482) and mutant (BCRPR482T) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively.


Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRPR482, in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRPR482 and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRPR482T.


The synthetic taxane derivatives ortataxel and tRA96023 are broad-spectrum ABC protein modulators. Further studies will seek to identify a noncytotoxic synthetic taxane that modulates Pgp, MRP-1 and BCRP.


Taxanes P-glycoprotein Multidrug resistance protein Breast cancer resistance protein Modulation 


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Hans Minderman
    • 1
  • Tracy A. Brooks
    • 2
  • Kieran L. O’Loughlin
    • 1
  • Iwao Ojima
    • 3
  • Ralph J. Bernacki
    • 2
  • Maria R. Baer
    • 1
    • 2
  1. 1.Leukemia Section, Department of MedicineRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of Pharmacology and TherapeuticsRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Department of ChemistryState University of New York at Stony BrookStony BrookUSA

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