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Cytotoxicity of adriamycin, idarubicin, and vincristine in acute myeloid leukemia: Chemosensitization by verapamil in relation to P-glycoprotein expression

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Summary

A 4-day colorimetric tetrazolium dye (MTT) assay was used to assess the cytotoxicity of adriamycin (ADM), vincristine (VCR), and idarubicin (IDA) in blasts isolated from 37 patients with newly diagnosed and pretreated acute myeloid leukemia (AML). The effect of verapamil (VRP) as a chemosensitizer was studied in relation to the expression of the membrane efflux pump P-glycoprotein (PGP) as determined by a semiquantitative flow-cytometric procedure. A slight positive correlation was found between the fraction of cells expressing PGP and the ID50 values for ADM and VCR, but not between cellular PGP content and sensitivity to IDA. The overall data showed no significant sensitization effect of VRP. However, in specimens with more than 10% cells expressing PGP, 2μM VRP sensitized cells to ADM and VCR significantly. The median of sensitization ratios (SRs), i.e., the ratios of cytotoxic drug ID50 in the absence/presence of VRP, were 1.89 and 2.0, respectively. No sensitizing effect of VRP on the cytotoxicity of IDA was observed. Related to the clinical status, the median fraction of PGP-positive blasts was elevated fourfold in pretreated patients (n=16) in comparison to patients with de novo AML (n=19). No differences in ID50 values were observed between newly diagnosed and pretreated patients. However, SRs for ADM and VCR were higher in samples of pretreated patients compared with de novo AML. PGP-mediated cellular drug resistance may thus be circumvented in leukemic blasts by application of chemosensitizers or, potentially, alternative anthracyclines.

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Authors and Affiliations

  1. Department of Medical Oncology, University of Essen Medical School, W-4300, Essen 1, Germany

    M. R. Müller, C. Boogen, M. R. Nowrousian & S. Seeber

  2. Institute of Cell Biology (Cancer Research), West German Cancer Center Essen, University of Essen Medical School, W-4300, Essen 1, Germany

    K. Lennartz & M. F. Rajewsky

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  1. M. R. Müller
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  2. K. Lennartz
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  3. C. Boogen
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  5. M. F. Rajewsky
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  6. S. Seeber
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Müller, M.R., Lennartz, K., Boogen, C. et al. Cytotoxicity of adriamycin, idarubicin, and vincristine in acute myeloid leukemia: Chemosensitization by verapamil in relation to P-glycoprotein expression. Ann Hematol 65, 206–212 (1992). https://doi.org/10.1007/BF01703946

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  • DOI: https://doi.org/10.1007/BF01703946

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