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Cancer Chemotherapy and Pharmacology

, Volume 40, Issue 3, pp 245–250 | Cite as

Resistance to paclitaxel mediated by P-glycoprotein can be modulated by changes in the schedule of administration

  • Zhirong Zhan
  • Stefania Scala
  • Anne Monks
  • Curtis Hose
  • Susan Bates
  • T. Fojo
ORIGINAL ARTICLE

Abstract

Purpose: Increasing use of paclitaxel in clinical oncology has stimulated interest in its mechanisms of resistance and ways to overcome these. Studies were performed with paclitaxel to determine the role of P-glycoprotein in drug sensitivity, and the effect of schedule on relative resistance. We have previously reported that prolonged exposure to P-glycoprotein substrates decreases relative resistance in multidrug resistant cells. Methods: Using both unselected and drug-selected cell lines, cross-resistance and cytotoxicity reversal studies using cyclosporin A were performed. In multidrug-resistant cells, cross-resistance was evaluated after 3-, 24-, and 96-h exposures to paclitaxel. Results: Cross-resistance to paclitaxel in P-glycoprotein-expressing sublines was shown to be comparable to that of other drugs transported by P-glycoprotein. Sensitivity to paclitaxel could be modulated by cyclosporin A in unselected cell lines expressing P-glycoprotein and not in P-glycoprotein-negative cell lines. Resistance to paclitaxel was reduced tenfold by increasing the duration of exposure in P-glycoprotein-expressing cells. This effect was not observed in a paclitaxel-resistant cell line which does not express P-glycoprotein. Conclusions: These studies extend observations on the schedule dependence of paclitaxel cytotoxicity and the role of P-glycoprotein in mediating paclitaxel sensitivity. The schedule dependence of relative resistance suggests that infusional paclitaxel may help in overcoming P-glycoprotein-mediated resistance.

Key words Paclitaxel   Drug resistance   Resistance reversal   P-glycoprotein   Scheduledependence 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • Zhirong Zhan
    • 1
  • Stefania Scala
    • 1
  • Anne Monks
    • 2
  • Curtis Hose
    • 2
  • Susan Bates
    • 1
  • T. Fojo
    • 1
  1. 1.Medicine Branch, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA Fax (301) 402-0172US
  2. 2.Program Resources, Inc./Syn Corp., NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USAUS

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