Abstract
We have previously described a mitoxantrone-resistant MCF7 cell line that is cross-resistant to topotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11), and 9-aminocamptothecin, but not to camptothecin. A novel mechanism that resulted in decreased topotecan accumulation in MCF7/MX cells was proposed (Yang et al. Cancer Res 55: 4004-4009, 1995). We now have developed a topotecan-resistant cancer cell line from wild-type MCF7 cells. MCF7/TPT300 cells were 68.9-fold resistant to topotecan, 68.3-fold to 10-hydroxy-7-ethylcamptothecin (SN-38), and 116-fold to mitoxantrone, but only 4.1-fold to camptothecin. Topotecan efflux was increased in MCF7/TPT300 cells compared with MCF7/WT cells, and this increase was reversed upon ATP depletion by sodium azide, suggesting an energy-dependent drug efflux mechanism. However, MCF7/TPT300 cells did not overexpress P-glycoprotein or the multidrug resistance-associated protein (MRP1). In contrast, overexpression of the breast cancer resistance protein (BCRP/MXR/ABCP) was observed in MCF7/TPT300 cells as well as DNA topoisomerase I down-regulation. Our data suggest that enhanced topotecan efflux contributes partly to topotecan resistance in MCF7/TPT300 cells, possibly mediated by BCRP/MXR/ABCP.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / biosynthesis*
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ATP-Binding Cassette Transporters / genetics
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents / pharmacology
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Biological Transport
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Breast Neoplasms / enzymology
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Breast Neoplasms / metabolism*
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DNA Topoisomerases, Type I / biosynthesis
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DNA Topoisomerases, Type II / biosynthesis
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DNA-Binding Proteins / biosynthesis
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Multidrug Resistance-Associated Proteins*
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MutS Homolog 3 Protein
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Topotecan / pharmacology*
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Tumor Cells, Cultured
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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DNA-Binding Proteins
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MSH3 protein, human
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Multidrug Resistance-Associated Proteins
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MutS Homolog 3 Protein
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Neoplasm Proteins
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Topotecan
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Adenosine Triphosphate
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DNA Topoisomerases, Type I
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DNA Topoisomerases, Type II
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multidrug resistance-associated protein 1