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JNCI Journal of the National Cancer Institute 1989 81(24):1887-1892; doi:10.1093/jnci/81.24.1887
© 1989 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 81, No. 24, 1887-1892, December 20, 1989
© 1989 Oxford University Press

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

Gerrit J. Schuurhuis*, Henricus J. Broxterman, Andres Cervantes, Theodorus H. M. van Heijningen, Johannes H. M. de Lange, Jan P. A. Baak, Herbert M. Pinedo, Jan Lankelma

Department of Medical Oncology, Free University Hospital Amsterdam, The Netherlands
Department of Quantitative Pathology, Free University Hospital Amsterdam, The Netherlands
Department of Hematology and Medical Oncology, University Hospital Valencia, Spain

*Correspondence to: Dr. Gerrit J. Schuurhuis, Department of Medical Oncology, Free University Hospital, BR 232, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.

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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