Idarubicin Activity Against Multidrug-Resistant (mdr-1+) Cells is Increased by Cyclosporin A

  • B. Chiodini
  • R. Bassar
  • G. Borleri
  • T. Lerede
  • T. Barbui
Conference paper
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 39)

Abstract

Multidrug resistance related to functional overexpression of P-170 glycoprotein (mdr-1 gene) is often responsible for treatment failure in acute leukaemia. Attempts to restore drug sensitivity with revertants and less vulnerable drugs are underway. We compared the ability of cyclosporin A to modulate mdr-1 resistance of T-lymphoblastic CEM cells to daunorubicin and idarubicin. To obtain clinically useful informations, experimental conditions reproduced partially in vivo pharmacology (drug peak plasma levels, alcohol metabolites, exposure times) of a single intravenous bolus with daunorubicin 45 mg/m2 or idarubicin 10–12 mg/m2, plus cyclosporin A 16 mg/kg/d given as continuous infusion (List schedule). Study methods were cytofluorimetry for detection of anthracycline early uptake, retention and pro-apoptotic effects (binding to fluoresceinated annexin V) at the single cell level, and the standard MTT growth inhibition assay for cytotoxicity. The results showed greater drug uptake/retention and apoptotic rates with idarubicin than with daunorubicin, with a further increase by cyclosporin A. MTT results were in favour of idarubicin with or without cyclosporin A, and greatly influenced by cyclosporin A itself. Altogether, study results in mdr-1+ cells with idarubicin/idarubicinol at 100/20 ng/ml, corresponding to levels achievable in vivo with a single idarubicin dose ≥ 12 mg/m2, were in the range of those obtained with standard-dose daunorubicin in mdr1-cells. These findings underscore the potential usefulness of an idarubicin plus cyclosporin A combination in mdr-1+ leukaemias, and prompt further studies on associations with other modulators of P-170 functional activity.

Keywords

Leukemia Oncol Cyclosporin Diol Propanol 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • B. Chiodini
    • 1
  • R. Bassar
    • 1
  • G. Borleri
    • 1
  • T. Lerede
    • 1
  • T. Barbui
    • 1
  1. 1.Haematology DepartmentOspedali RiunitiBergamoItaly

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