Characterization of tumor cell resistance to 4'-deoxy-4'-iododoxorubicin developed in Ehrlich ascites cells in vivo.

Abstract

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'-iododoxorubicin (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.

• Authors: E Friche, M K Danks, W T Beck
• Journal: Cancer research (Cancer Res) Vol. 52 Issue 20 Pg. 5701-6 (Oct 15 1992) ISSN: 0008-5472 [Print] United States
• PMID: 1356619 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Affinity Labels
• Azides
• DNA-Binding Proteins
• Dihydropyridines
• Macromolecular Substances
• Membrane Glycoproteins
• Neoplasm Proteins
• azidopine
• 4'-deoxy-4'-iododoxorubicin
• Doxorubicin
• Teniposide
• DNA Topoisomerases, Type II
• Daunorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Affinity Labels
• Animals
• Azides (metabolism)
• Carcinoma, Ehrlich Tumor (drug therapy, metabolism)
• Cell Line
• DNA Topoisomerases, Type II (analysis, pharmacology)
• DNA-Binding Proteins (drug effects)
• Daunorubicin (pharmacokinetics)
• Dihydropyridines (metabolism)
• Doxorubicin (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
• Drug Resistance
• Macromolecular Substances
• Membrane Glycoproteins (analysis)
• Mice
• Neoplasm Proteins (metabolism)
• Teniposide (pharmacology)
• Tumor Cells, Cultured