Abstract
Transfection of multidrug resistance proteins (MRPs) MRP1 and MRP2 in human ovarian carcinoma 2008 cells conferred a marked level of resistance to short-term (1-4 h) exposure to the polyglutamatable antifolates methotrexate (MTX; 21-74-fold), ZD1694 (4-138-fold), and GW1843 (101-156-fold). Evidence for MRP-mediated antifolate efflux relies upon the following findings: (a) a 2-3.3-fold lower accumulation of [3H]MTX and subsequent reduced formation of long-chain polyglutamate forms of MTX; (b) reversal of MTX resistance by probenecid in both transfectants, and (c) ATP-dependent uptake of [3H]MTX in inside-out vesicles of MRP1 and MRP2 transfectants. This report provides a mechanistic basis for resistance to polyglutamatable antifolates through an MRP-mediated drug extrusion.
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 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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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 / antagonists & inhibitors
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Adenosine Triphosphate / metabolism
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Antimetabolites, Antineoplastic / metabolism*
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Antimetabolites, Antineoplastic / pharmacology
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Drug Resistance, Multiple* / genetics
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Drug Resistance, Neoplasm / genetics
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Female
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Folic Acid Antagonists / metabolism*
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Folic Acid Antagonists / pharmacology
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Glutamates / metabolism
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Humans
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Indoles / metabolism
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Indoles / pharmacology
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Isoindoles
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Methotrexate / metabolism
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Methotrexate / pharmacology
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism*
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Quinazolines / metabolism
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Quinazolines / pharmacology
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Thiophenes / metabolism
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Thiophenes / pharmacology
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Transfection
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Tumor Cells, Cultured / drug effects
Substances
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP-Binding Cassette Transporters
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Antimetabolites, Antineoplastic
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Folic Acid Antagonists
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Glutamates
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Indoles
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Isoindoles
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Quinazolines
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Thiophenes
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1843U89
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Adenosine Triphosphate
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multidrug resistance protein 3
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raltitrexed
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Methotrexate