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

Autor: Candeil L; CNRS-UMR 5160, Centre de Recherche en Cancérologie, CRLC Val d'Aurelle, Montpellier, France., 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
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2004 May 10; Vol. 109 (6), pp. 848-54.
DOI: 10.1002/ijc.20032
Abstrakt: 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 Ko143 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.
(Copyright 2004 Wiley-Liss, Inc.)
Databáze: MEDLINE
Externí odkaz: