Trabectedin (ET-743, Yondelis) is a substrate for P-glycoprotein, but only high expression of P-glycoprotein confers the multidrug resistance phenotype.

Investigational New Drugs
J H BeumerOlaf van Tellingen

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.

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Citations

Feb 25, 2009·Investigational New Drugs·J H BeumerO van Tellingen
Jun 6, 2009·Expert Review of Anticancer Therapy·Laurence BoudouPhilippe A Cassier
May 23, 2014·Drug Discovery Today. Technologies·Benedetta ColmegnaMaurizio D'Incalci
Jul 12, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Solida LongMadalena M M Pinto
Oct 2, 2008·Cancer Chemotherapy and Pharmacology·Zhenfeng DuanFrancis J Hornicek
Aug 18, 2009·The Oncologist·Meredith K ChukElizabeth Fox

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