Membrane transport changes in an adriamycin-resistant murine leukemia cell line and in its sensitive parental cell line.
Multidrug resistance in cancer chemotherapy occurs when cells develop resistance towards structurally and functionally unrelated drugs. It is speculated that alteration of some fundamental process(es) in the cells leads to the development of multidrug resistance. The sodium pump activity of murine leukemia cell lines P388/S (sensitive) and P388/ADR (resistant) was measured and found to be different in the two cell lines. The rate of sodium pumping, i.e., the ouabain-sensitive rubidium uptake, was consistently lower in the resistant cells compared to their parental controls. Uptake of adriamycin was lower in the resistant cells. Depolarizing the cells with potassium chloride or by inhibiting the pump with ouabain increased the adriamycin uptake in the sensitive cells but not in the resistant cells. Adriamycin did not have any acute effects on the sodium pump activity. It is concluded that the development of drug resistance in cell line P388 is associated with a decrease in sodium pump activity and a lack of depolarization-induced adriamycin uptake; these processes may be causally linked via alterations in cytosolic calcium concentration.
Bose
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Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
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D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D010042:Ouabain / Q000494:pharmacology; D012413:Rubidium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D010042:Ouabain; D004317:Doxorubicin; D012964:Sodium; D014700:Verapamil; D012413:Rubidium