Abstract
Trabectedin (ET-743, Yondelis) is a novel anticancer drug currently undergoing phase II and III investigations. There are various and conflicting reports whether trabectedin is a substrate for P-glycoprotein (P-gp), an important factor in drug disposition and multi-drug resistance (MDR). We have now unambiguously shown that trabectedin is a P-gp substrate by investigating vectorial transport over monolayers of LLC-PK1 pig kidney and Madine-Darby Canine kidney (MDCK) cells and the mdr1a and/or MDR1 transfected subclones. We further characterized the cytotoxic effects and cellular accumulation of trabectedin in these cell lines as well as in a panel of other cell lines with high or moderate expression levels of P-gp. Trabectedin displayed the typical MDR phenotype only in highly P-gp expressing cell lines, but not in cell lines with expression levels more closely conforming to clinical samples, suggesting that P-gp will not confer resistance to trabectedin in cancer patients.
MeSH terms
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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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Animals
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Antineoplastic Agents, Alkylating / pharmacology
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Biological Transport / drug effects
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Carbon Radioisotopes
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Cell Line
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Cell Membrane Permeability / drug effects
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Cell Survival / drug effects
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Dibenzocycloheptenes / pharmacology
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Dioxoles / metabolism
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Dioxoles / pharmacology*
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Drug Resistance, Multiple*
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Drug Resistance, Neoplasm
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Humans
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Inhibitory Concentration 50
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Intracellular Fluid / chemistry
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Intracellular Fluid / drug effects
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Intracellular Fluid / metabolism
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LLC-PK1 Cells
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Mice
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Paclitaxel / pharmacology
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Quinolines / pharmacology
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Swine
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Tetrahydroisoquinolines / metabolism
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Tetrahydroisoquinolines / pharmacology*
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Trabectedin
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Transfection / methods
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents, Alkylating
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Carbon Radioisotopes
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Dibenzocycloheptenes
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Dioxoles
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Membrane Transport Proteins
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Quinolines
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Tetrahydroisoquinolines
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zosuquidar trihydrochloride
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Trabectedin
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Paclitaxel