Establishment and characterization of adriamycin-resistant human colorectal adenocarcinoma HCT-15 cell lines with multidrug resistance

被引:39
作者
Uchiyama-Kokubu, N [1 ]
Watanabe, T [1 ]
机构
[1] Novartis Pharma KK, Tsukuba Res Inst, Tsukuba, Ibaraki 3002611, Japan
关键词
adriamycin; human colorectal adenocarcinoma HCT-15; multidrug resistance; multidrug-resistance-associated protein; lung-resistance-associated protein; P-glycoprotein;
D O I
10.1097/00001813-200110000-00009
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The multidrug resistance (MDR) phenotype, either intrinsic and/or acquired, is discussed in relation to several MDR-associated markers such as P-glycoprotein (P-gp) encoded by mdr1, multidrug-resistance-associated protein (MRP) encoded by MRP and lung-resistance-associated protein (LRP) encoded by LRP. Well-characterized in vitro models are required to elucidate the mechanisms of MDR. The aim of the present study is the establishment of a drug-resistant subline from human colorectal adenocarcinoma HCT-15 that intrinsically expresses moderate levels of P-gp, MRP and LRP. Three adriamycin-resistant sublines (HCT-15/ADM1, HCT-15/ADM2 and HCT-15/ADM2-2) were established by stepwise exposure in growth medium that was supplemented with 25-200 ng/ml adriamycin-resulting in a 2.2- to 7.8-fold increase in IC50 values by using the XTT assay. They were cross-resistant to MDR-related drugs, epirubicin, mitoxantrone, vincristine, etoposide and taxol, but not the MDR-unrelated drug, mytomycin C. The resistance to adriamycin was confirmed in vivo by a lack of sensitivity in athymic nude mice. Gene expression data for mdr1/P-gp, MRP/MRP and LRP/LRP on both mRNA and protein levels demonstrated that the molecules contributing to MDR in resistant sublines are mainly P-gp and partially MRP. The newly established adriamycin-resistant sublines of HCT-15 will provide clinically relevant tools to investigate how to overcome drug resistance and elucidate possible mechanisms of acquired MDR in human colon cancer. [(C) 2001 Lippincott Williams & Wilkins.].
引用
收藏
页码:769 / 779
页数:11
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