Trabectedin (ET-743, Yondelis ) is a substrate for P-glycoprotein, but only high expression of P-glycoprotein confers the multidrug resistance phenotype.
Beumer JH, Buckle T, Ouwehand M, Franke NE, Lopez-Lazaro L, Schellens JH, Beijnen JH, van Tellingen O.
Invest New Drugs. 2006 Apr
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
Trabectedin (ET-743, Yondelistrade mark) 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.