Decreased resistance to N,N-dimethylated anthracyclines in multidrug-resistant Friend erythroleukemia cells.

Abstract

Doxorubicin-resistant Friend erythroleukemia cells, line F4-6 ADM2R, were selected by exposure of wild-type F4-6 cells to doxorubicin concentrations of up to 1 microgram/ml. In these cells, increased expression of multidrug resistance (MDR) genes was demonstrated by Northern blot analysis. The growth-inhibitory effect of doxorubicin, daunorubicin, N,N-dimethyldoxorubicin, N,N-dimethyldaunorubicin, morpholinodoxorubicin, and pyrromycin was comparatively investigated in resistant and wild-type cells. The doxorubicin-resistant F4-6 cells showed approx. 200-fold resistance to doxorubicin and about 100-fold resistance to daunorubicin with respect to the drug-sensitive counterpart. A dramatic decrease in resistance was observed for the N,N-dimethylated derivatives of doxorubicin and daunorubicin as well as for the N,N-dimethylated natural anthracycline pyrromycin and for morpholinodoxorubicin. Uptake studies using [14C]-daunorubicin and [14C]-N,N-dimethyldaunorubicin in resistant F4-6 cells showed a decreased accumulation of daunorubicin but no significant reduction in N,N-dimethyldaunorubicin accumulation as compared with the wild-type cells. Treatment with verapamil led to increased intracellular levels of daunorubicin in resistant cells, whereas an excess of N,N-dimethyldaunorubicin did not have this effect. Thus, the decreased resistance of the doxorubicin-resistant F4-6 cells to the N-alkylated anthracyclines may at least in part be due to a reduced affinity of these compounds for the efflux pump. The results indicate that the dimethylation of the amino group of the anthracycline sugar moiety and its incorporation within a morpholinyl ring may overcome MDR by similar mechanisms.

• Authors: A Schaefer, J Westendorf, K Lingelbach, C A Schmidt, D L Mihalache, A Reymann, H Marquardt
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 31 Issue 4 Pg. 301-7 ( 1993) ISSN: 0344-5704 [Print] Germany
• PMID: 8422694 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents
• RNA, Neoplasm

Topics

• Antibiotics, Antineoplastic (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Blotting, Northern
• Cell Division (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance
• Friend murine leukemia virus (drug effects)
• Leukemia, Erythroblastic, Acute (drug therapy)
• RNA, Neoplasm (drug effects)
• Structure-Activity Relationship
• Tumor Cells, Cultured (drug effects)