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Decreased DNA Topoisomerase II in Daunorubicin-resistant Ehrlich Ascites Tumor Cells¹

Department of Medicine and Hematology L, 4042, Rigshospitalet-University Hospital, 9, Blegdamsvej, DK-2100 Copenhagen, Denmark [E. F.]; Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 [M. K. D., C. A. S., W. T. B.]; and Department of Pharmacology, College of Medicine, University of Tennessee, Memphis, Tennessee 38168 [W. T. B.]

We have previously shown that the multidrug-resistant EHR2/DNR+ cells, which overexpress P-glycoprotein, accumulate only about 20–30% of daunorubicin at steady state compared to the sensitive cells. These cells have been thought to be a "pure" P-glycoprotein cell line. We now report that the EHR2/DNR+ cells exhibit decreased DNA topoisomerase II catalytic activity. We also found that the amount of immunoreactive DNA topoisomerase II from these cells is about one-third that seen in the drug-sensitive cell line. In agreement with the decreased activity and amount of topoisomerase II, the number of DNA-protein complexes stabilized by teniposide (VM-26) was reduced by about 50% in nuclear extracts from EHR2/DNR+ cells. Furthermore, using an intact cell assay for DNA protein complexes, we found that the VM-26-stimulated complexes formed in the drug-resistant cells never reached the level seen in the drug-sensitive cells. Verapamil and Cremophor EL both block P-glycoprotein-mediated efflux of "natural product" drugs and increase their accumulation in resistant cells. Coincubation of the EHR2/DNR+ cells with VM-26 and either of these modulators increased the number of complexes formed in the resistant cells. However, neither modulator increased the number of topoisomerase II-DNA complexes in the drug-resistant cells to the level seen in the EHR2 cells. We conclude that the resistance of EHR2/DNR+ cells is due in part to reduced amounts of DNA topoisomerase II. Furthermore, we note that a single cell line can express features of both P-glycoprotein-associated multidrug resistance and altered topoisomerase II-associated multidrug resistance.

¹ Supported in part by Research Grants CA-30103 and CA-47941, Cancer Center Support (CORE) Grant CA-21765, all from the National Cancer Institute, Bethesda, MD, and in part by American Lebanese Syrian Associated Charities. Travel grants to E.F. were provided by Farmitalia, Carlo Erba Division, Denmark, and Emmy Lange b. Kramp Foundation, University of Copenhagen.

² To whom requests for reprints should be addressed, at Department of Medicine and Hematology, L 4042, Rigshospitalet-University Hospital, 9, Blegdamsvej, DK-2100 Copenhagen, Denmark.

Received 3/22/91. Accepted 6/ 7/91.

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