ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases

被引:139
作者
Candeil, L
Gourdier, I
Peyron, D
Vezzio, N
Copois, V
Bibeau, F
Orsetti, B
Scheffer, GL
Ychou, M
Khan, QA
Pommier, Y
Pau, B
Martineau, P
Del Rio, M
机构
[1] CRLC Val dAurelle, Ctr Rech Cancerol, CNRS UMR 5160, F-34298 Montpellier 5, France
[2] CRLC Val dAurelle, Serv Anatomopathol & Oncol Digest, F-34298 Montpellier 5, France
[3] NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA
[4] Free Univ Amsterdam Hosp, Dept Pathol, Amsterdam, Netherlands
[5] CRLC Val dAurelle, Ctr Rech Cancerol, INSERM E229, F-34298 Montpellier 5, France
关键词
colorectal cancer; ABCG2; SN38; drug resistance;
D O I
10.1002/ijc.20032
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Kol43 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:848 / 854
页数:7
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