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Relationship of VP-16 to the Classical Multidrug Resistance Phenotype¹

Department of Pathology, Sundby Hospital, 2300 Copenhangen S (M. S.); Departments of Internal Medicine L (E. F.) and Oncology (P. B. J.) Rigshospitalet, 2100 Copenhagen Ø; and Department of Biochemistry C, The Panum Institute, DK-2200 Copenhagen N (E. J. F. D.), Denmark

The classical multidrug resistance (MDR) phenotype is characterized by cross-resistance between a number of chemically unrelated drugs due to an increased efflux across the plasma membrane via a P-glycoprotein-mediated mechanism. The epipodophyllotoxin derivatives etoposide (VP-16) and teniposide (VM-26) are usually included among the drugs recognized by this MDR phenotype, and the MDR EHR2/DNR cell line is >50-fold cross-resistant to VP-16. The steady-state accumulation of VP-16 in EHR2/DNR cells is only half that of wild-type EHR2 cells, and deprivation of energy by sodium azide surprisingly increased accumulation to a similar extent in both sublines. Efflux was rapid (halflife of 32–35 s) and similar in both sublines, while initial influx was markedly lower in the resistant cells. The temperature coefficients over 10°C for VP-16 in- and efflux indicated passive transport in both sublines. In agreement with this finding, up to 10-fold molar excess (50 µM) VM-26 had no effect on VP-16 accumulation in MDR cells. VP-16 at a 100-fold molar excess inhibited azidopine photoaffinity labeling of P-glycoprotein by only 30% and vincristine binding to plasma membrane vesicles from EHR/DNR cells by 45%. However, VP-16 itself did not differentially bind to plasma membrane vesicles from EHR2 and EHR2/DNR cells. Finally, neither VP-16 accumulation nor cytotoxicity in EHR2/DNR cells were increased to the same degree as for daunorubicin and vincristine by verapamil, and the modulation was similar in wild-type and resistant cells. Thus, although VP-16 may be a substrate for P-glycoprotein, its other transport characteristics such as rapid diffusion and sensitivity to membrane perturbation in wild-type cells lessen any effect of P-glycoprotein-mediated efflux, resulting in a lack of differential modulation by verapamil. These results may be considered when planning clinical trials involving MDR modulators and epipodophyllotoxin derivatives.

¹ Supported by Grants 90-044 and 91-012 from the Danish Cancer Society, The Katrine and Vigo Skovgaard Foundation, The Erik Berg Foundation, and the Hojmosegaard Foundation.

² To whom requests for reprints should be addressed, at Department of Pathology, Sundby Hospital, DK-2300 Copenhagen S, Denmark.

Received 2/11/91. Accepted 3/11/92.

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