Quantitative Determination of Factors Contributing to Doxorubicin Resistance in Multidrug-Resistant Cells

Authors:
  • HBHenricus J. Broxterman
    Henricus J. Broxterman
  • THTheodorus H. M. van Heijningen
    Theodorus H. M. van Heijningen
  • JLJohannes H. M. de Lange
    Johannes H. M. de Lange
  • JBJan P. A. Baak
    Jan P. A. Baak
  • HPHerbert M. Pinedo
    Herbert M. Pinedo
  • JLJan Lankelma
    Jan Lankelma
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Abstract
There is a large discrepancy between the changes in drug accumulation and the changes in drug cytotoxicity that accompany development of anthracycline resistance in multidrug-resistant cells. In our study, a quantitative relationship has been established between reversal of multidrug resistance by resistance modifiers and a concomitant decrease in intracellular levels of doxorubicin measured at equitoxic concentrations (IC50) in CHRC5 and 2780AD multidrug-resistant cells. (IC50 = concentration required for 50% growth inhibition.) We have demonstrated that resistance modifiers like verapamil and Ro 11–2933/001 act by increasing the effectiveness of intracellular doxorubicin, apparently by inducing redistribution of the drug from the cytoplasm to the nucleus of a multidrug-resistant cell, as shown by quantitative fluorescence microscopy. At complete reversal of resistance, as measured directly or inferred by extrapolation, the amount of intracellular doxorubicin at the IC50 as well as the ratio of nuclear doxorubicin to cytoplasmic doxorubicin were the same as those in sensitive cells. These results offer an explanation for the frequently observed discrepancies between drug accumulation and cytotoxicity and also show quantitatively that a decrease in drug accumulation and a change in intracellular drug distribution together are the only determinants of doxorubicin resistance in the multidrug-resistant cells studied. [J Natl Cancer Inst 81: 1887–1892, 1989]

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