Abstract
A drug resistant series of sublines were developed by treating the human leukaemia CCRF-CEM cell line with 16-1000 ng/ml of the anthracycline, epirubicin. The sublines developed resistance in two stages, neither involving detectable levels of P-glycoprotein. Treatment with up to 50 ng/ml epirubicin produced sublines with cross resistance limited to the anthracyclines and etoposide. Treatment with 100-1000 ng/ml epirubicin produced sublines with increased expression of the mrp gene, increased resistance to the anthracyclines and etoposide, additional cross resistance to vincristine and colchicine, decreased drug accumulation and reversal of resistance by verapamil and by buthionine sulphoximine (BSO; an inhibitor of glutathione synthesis). Our results indicate an interaction between MRP and glutathione metabolism as a mechanism for multidrug resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Buthionine Sulfoximine
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Cell Line
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Cell Survival / drug effects
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Drug Resistance, Multiple*
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Epirubicin / pharmacology*
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Gene Expression
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Humans
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In Vitro Techniques
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Methionine Sulfoximine / analogs & derivatives
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Methionine Sulfoximine / pharmacology
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Multidrug Resistance-Associated Proteins
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RNA, Messenger / genetics
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RNA, Neoplasm / genetics
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Tumor Cells, Cultured
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Verapamil / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP-Binding Cassette Transporters
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Multidrug Resistance-Associated Proteins
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RNA, Messenger
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RNA, Neoplasm
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Methionine Sulfoximine
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Epirubicin
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Buthionine Sulfoximine
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Verapamil