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. © 2004 Wiley-Liss, Inc. Key words: colorectal cancer; ABCG2; SN38; drug resistanceChemotherapeutic drug resistance is a frequent cause of treatment failure in colorectal cancer patients. Understanding the cellular mechanisms that lead to this resistance should permit an improvement in the treatment of colorectal cancer. Irinotecan (CPT-11), a semisynthetic water-soluble derivative of camptothecin, is widely used for the treatment of metastatic colon cancer. 1 CPT-11 is a prodrug converted by carboxylesterases into its active form, SN38. 2 Like other camptothecin derivatives, SN38 exerts its cytotoxic activity through the inhibition of topoisomerase I. Human topoisomerase I is a 100 kDa nuclear enzyme needed for replication and transcription and causing single strand breaks in DNA, thus permitting relaxation of supercoiled DNA. 3 SN38 interferes with topoisomerase I function by forming stable ternary complexes at the DNA breakage points and stopping the topoisomerase I-mediated religation. 4 Cellular resistance to camptothecin derivatives can result from a decrease in cellular drug accumulation, alterations in the structure or location of topoisomerase I, changes in the cellular response to the drug-DNA-enzyme ternary complex formation 5 or increased glucuronidation of SN38, resulting in an inactivation of the drug. 6 Members of the ATP-binding cassette (ABC) transporters, notably MDR1 (ABCB1) and MRP1 (ABCC1), confer resistance to chemotherapeutic drugs by active drug efflux. 7,8 Recently, a new member of this family, the ABCG2 transporter also called BCRP 9 or ABCP 10 or MXR 11 has been discovered. This gene, ...
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