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

Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

Keywords

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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