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Decreased resistance toN,N-dimethylated anthracyclines in multidrug-resistant Friend erythroleukemia cells

  • Original Articles
  • Multidrug Resistance, Anthracyclines, Friend Cells
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Summary

Doxorubicin-resistant Friend erythroleukemia cells, line F4–6 ADM2R, were selected by exposure of wild-type F4-6 cells to doxorubicin concentrations of up to 1 μg/ml. In these cells, increased expression of multidrug resistance (MDR) genes was demonstrated by Northern blot analysis. The growth-inhibitory effect of doxorubicin, daunorubicin,N,N-dimethyldoxorubicin,N,N-dimethyldaunorubicin, morpholinodoxorubicin, and pyrromycin was comparatively investigated in resistant and wild-type cells. The doxorubicin-resistant F4-6 cells showed approx. 200-fold resistance to doxorubicin and about 100-fold resistance to daunorubicin with respect to the drug-sensitive counterpart. A dramatic decrease in resistance was observed for theN,N-dimethylated derivatives of doxorubicin and daunorubicin as well as for theN,N-dimethylated natural anthracycline pyrromycin and for morpholinodoxorubicin. Uptake studies using [14C]-daunorubicin and [14C]-N,N-dimethyldaunorubicin in resistant F4-6 cells showed a decreased accumulation of daunorubicin but no significant reduction inN,N-dimethyldaunorubicin accumulation as compared with the wild-type cells. Treatment with verapamil led to increased intracellular levels of daunorubicin in resistant cells, whereas an excess ofN,N-dimethyldaunorubicin did not have this effect. Thus, the decreased resistance of the doxorubicin-resistant F4-6 cells to theN-alkylated anthracyclines may at least in part be due to a reduced affinity of these compounds for the efflux pump. The results indicate that the dimethylation of the amino group of the anthracycline sugar moiety and its incorporation within a morpholinyl ring may overcome MDR by similar mechanisms.

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Authors and Affiliations

  1. Department of Pharmacology, University of Hamburg Medical School, D-2000, Hamburg, Germany

    András Schaefer, Johannes Westendorf, Klaus Lingelbach, Doina-Lucia Mihalache, Andreas Reymann & Hans Marquardt

  2. Fraunhofer Institute of Toxicology and Molecular Biology, D-2000, Hamburg, Germany

    András Schaefer, Johannes Westendorf, Klaus Lingelbach, Doina-Lucia Mihalache, Andreas Reymann & Hans Marquardt

  3. Laboratory of Immunibiochemistry, University Hospital Rudolf Virchow, D-1000, Berlin, Germany

    Christian A. Schmidt

  4. Department of Toxicology, University of Hamburg Medical School, Grindelallee 117, D-2000, Hamburg 13, Germany

    András Schaefer, Johannes Westendorf, Klaus Lingelbach, Doina-Lucia Mihalache, Andreas Reymann & Hans Marquardt

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Schaefer, A., Westendorf, J., Lingelbach, K. et al. Decreased resistance toN,N-dimethylated anthracyclines in multidrug-resistant Friend erythroleukemia cells. Cancer Chemother. Pharmacol. 31, 301–307 (1993). https://doi.org/10.1007/BF00685675

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