title: Trabectedin (ET-743, Yondelis) is a substrate for P-glycoprotein, but only high expression of P-glycoprotein confers the multidrug resistance phenotype.
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.
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Beumer
authors.forename: Tessa
authors.initials: T
authors.lastname: Buckle
authors.forename: Mariet
authors.initials: M
authors.lastname: Ouwehand
authors.forename: Niels E F
authors.initials: NE
authors.lastname: Franke
authors.forename: Luis
authors.initials: L
authors.lastname: Lopez-Lazaro
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004149:Dioxoles / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D007424:Intracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018374:LLC-PK1 Cells; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013552:Swine; D044005:Tetrahydroisoquinolines / Q000378:metabolism / Q000494:pharmacology*; D000077606:Trabectedin; D014162:Transfection / Q000379:methods
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018906:Antineoplastic Agents, Alkylating; D002250:Carbon Radioisotopes; D003986:Dibenzocycloheptenes; D004149:Dioxoles; D026901:Membrane Transport Proteins; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C095179:zosuquidar trihydrochloride; D000077606:Trabectedin; D017239:Paclitaxel