Beumer Jan-Hendrik, Buckle Tessa, Ouwehand Mariet, Franke Niels E F, Lopez-Lazaro Luis, Schellens Jan H M, Beijnen Jos H, van Tellingen Olaf
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
Invest New Drugs. 2007 Feb;25(1):1-7. doi: 10.1007/s10637-006-7773-9.
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.
曲贝替定（ET-743，商品名Yondelis）是一种新型抗癌药物，目前正处于II期和III期临床试验阶段。关于曲贝替定是否是P-糖蛋白（P-gp）的底物，存在各种相互矛盾的报道，而P-糖蛋白是药物代谢和多药耐药性（MDR）的一个重要因素。我们现在通过研究曲贝替定在LLC-PK1猪肾细胞和Madine-Darby犬肾（MDCK）细胞单层以及mdr1a和/或MDR1转染亚克隆上的向量转运，明确证明了曲贝替定是一种P-糖蛋白底物。我们进一步研究了曲贝替定在这些细胞系以及一组P-糖蛋白表达水平高或中等的其他细胞系中的细胞毒性作用和细胞蓄积情况。曲贝替定仅在P-糖蛋白高表达的细胞系中表现出典型的多药耐药表型，而在表达水平更接近临床样本的细胞系中则未表现出该表型，这表明P-糖蛋白不会使癌症患者对曲贝替定产生耐药性。
