Marchetti Serena, Oostendorp Roos L, Pluim Dick, van Eijndhoven Monique, van Tellingen Olaf, Schinkel Alfred H, Versace Richard, Beijnen Jos H, Mazzanti Roberto, Schellens Jan H
Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3307-13. doi: 10.1158/1535-7163.MCT-07-0461.
Lipophilic camptothecin derivatives are considered to have negligible affinity for breast cancer resistance protein (BCRP; ABCG2). Gimatecan, a new orally available 7-t-butoxyiminomethyl-substituted lipophilic camptothecin derivative, has been previously reported to be not a substrate for BCRP. Using a panel of in vitro models, we tested whether gimatecan is a substrate for BCRP as well as for P-glycoprotein (MDR1) or multidrug resistance protein 2 (MRP2; ABCC2), ATP-binding cassette drug efflux transporters involved in anticancer drug resistance, and able to affect the pharmacokinetics of substrate drugs. Cell survival, drug transport, accumulation, and efflux were studied in IGROV1 and (human BCRP overexpressing) T8 cells, Madin-Darby canine kidney II (MDCKII-WT, MDCKII-Bcrp1, MDCKII-MDR1, and MDCKII-MRP2), and LLCPK (LLCPK-WT and LLCPK-MDR1) cells. Competition with methotrexate uptake was studied in Sf9-BCRP membrane vesicles. In vitro, expression of BCRP resulted in 8- to 10-fold resistance to gimatecan. In Transwell experiments, gimatecan was transported by Bcrp1 and transport was inhibited by the BCRP/P-glycoprotein inhibitors elacridar and pantoprazole. Efflux of gimatecan from MDCKII-Bcrp1 cells was faster than in WT cells. In Sf9-BCRP membrane vesicles, gimatecan significantly inhibited BCRP-mediated transport of methotrexate. In contrast, gimatecan was not transported by MDR1 or MRP2. Gimatecan is transported by BCRP/Bcrp1 in vitro, although to a lesser extent than the camptothecin analogue topotecan. Implications of BCRP expression in the gut for the oral development of gimatecan and the interaction between gimatecan and other BCRP substrate drugs and/or inhibitors warrant further clinical investigation.
亲脂性喜树碱衍生物被认为对乳腺癌耐药蛋白（BCRP；ABCG2）的亲和力可忽略不计。吉美替康是一种新型的口服可用的7 -叔丁氧基亚氨基甲基取代的亲脂性喜树碱衍生物，此前有报道称它不是BCRP的底物。我们使用一组体外模型，测试吉美替康是否是BCRP以及P -糖蛋白（MDR1）或多药耐药相关蛋白2（MRP2；ABCC2）的底物，这些ATP结合盒式药物外排转运蛋白与抗癌药物耐药性有关，并且能够影响底物药物的药代动力学。在IGROV1细胞和（人BCRP过表达的）T8细胞、Madin - Darby犬肾II型细胞（MDCKII - WT、MDCKII - Bcrp1、MDCKII - MDR1和MDCKII - MRP2）以及LLCPK细胞（LLCPK - WT和LLCPK - MDR1）中研究了细胞存活、药物转运、积累和外排情况。在Sf9 - BCRP膜囊泡中研究了与甲氨蝶呤摄取的竞争情况。在体外，BCRP的表达导致对吉美替康产生8至10倍的耐药性。在Transwell实验中，吉美替康由Bcrp1转运，且转运受到BCRP/P -糖蛋白抑制剂艾拉司群和泮托拉唑的抑制。吉美替康从MDCKII - Bcrp1细胞中的外排比在野生型细胞中更快。在Sf9 - BCRP膜囊泡中，吉美替康显著抑制BCRP介导的甲氨蝶呤转运。相比之下，吉美替康不由MDR1或MRP2转运。吉美替康在体外由BCRP/Bcrp1转运，尽管其程度低于喜树碱类似物拓扑替康。BCRP在肠道中的表达对吉美替康口服开发的影响以及吉美替康与其他BCRP底物药物和/或抑制剂之间的相互作用值得进一步的临床研究。
