This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friche, E. Articles by Beck, W. T. Search for Related Content PubMed PubMed Citation Articles by Friche, E. Articles by Beck, W. T.

Characterization of Tumor Cell Resistance to 4'-Deoxy-4'-iododoxorubicin Developed in Ehrlich Ascites Cells in Vivo¹

Department of Medicine and Hematology, L 4042, Rigshospitalet-University Hospital, DK-2100 Copenhagen, Denmark [E. F.]; Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 [M. K. D., W. T. B.]; and Department of Pharmacology, College of Medicine, University of Tennessee, Memphis, Tennessee 38163 [W. T. B.]

Reduced drug accumulation is the most common functional change accompanying development of P-glycoprotein-associated multidrug resistance. One of our laboratories showed earlier that the anthracycline analogue 4'-deoxy-4'-lododoxorubicin (DIDOX) was accumulated to identical levels in Ehrlich ascites tumor (EHR2) and daunorubicin (DNR)-resistant EHR2/DNR⁺ cells (E. Friche, P. B. Jensen, T. Skovsgaard, and N. I. Nissen, J. Cell. Pharmacol., 1: 57–65, 1990). In this communication, we show that weekly treatment of EHR2-bearing mice with 4, 8, or 12 mg of DIDOX/kg/week led to the development of three DIDOX-resistant cell lines, EHR2/DIDOX-1, EHR2/DIDOX-2, and EHR2/DIDOX-3. The levels of DIDOX accumulation and retention and its outward transport were similar in the drug-sensitive and three drug-resistant cell lines. By contrast, the accumulation of the active DIDOX metabolite, 13-dihydro-DIDOX (13-OH-DIDOX), the parent compound doxorubicin, and daunorubicin were all decreased in proportion to the resistance of the cells. In EHR2/DIDOX-3 cells, the reduction in daunorubicin accumulation coincided with the development of P-glycoprotein as demonstrated by Western blot and flow cytometry with C219 antibody. DIDOX had no effect on the photolabeling of P-glycoprotein by [³H]azidopine, whereas 13-OH-DIDOX inhibited this labeling in a concentration-dependent manner. Subsequent analysis of topoisomerase II activities and amounts in EHR2/DIDOX-3 cells revealed decreased DNA topoisomerase II catalytic activity. The amounts of immunoreactive DNA topoisomerase II from EHR2/DIDOX-1, EHR2/DIDOX-2, and EHR2/DIDOX-3 cells were about 89%, 73%, and 52%, respectively, of that seen in the drug-sensitive cells. We also found that teniposide stabilized DNA-protein complexes in EHR2/DIDOX-3 but they never reached the level seen in EHR2 cells. Because it has been reported that DIDOX is rapidly metabolized to 13-OH-DIDOX, we postulate that the development of resistance to DIDOX in vivo is due in part to its metabolite, 13-OH-DIDOX, which is a substrate for plasma membrane glycoprotein, and in part to DIDOX, which is an inhibitor of topoisomerase II.

¹ Supported in part by the Martha Margrethe and Christian Hermansen Foundation; the University of Copenhagen; in part by Grants CA40570, CA30103, and CA21765 from the National Cancer Institute; and in part by the American Lebanese Syrian Associated Charities (W. T. B., M. K. D.).

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 4/22/92. Accepted 8/ 4/92.

This article has been cited by other articles:

				C. A. Felix, A. H. Walker, B. J. Lange, T. M. Williams, N. J. Winick, N.-K. V. Cheung, B. D. Lovett, P. C. Nowell, I. A. Blair, and T. R. Rebbeck Association of CYP3A4 genotype with treatment-related leukemia PNAS, October 27, 1998; 95(22): 13176 - 13181. [Abstract] [Full Text] [PDF]