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Expression and Functional Analyses of Breast Cancer Resistance Protein in Lung Cancer

Second Department of Internal Medicine [S. Kaw., M. O., K. Sh., K. N., J. T., Y. N., S. D., T. K., S. Ko.] and Department of Laboratory Medicine [H. S., K. Su., Y. Y., S. Kam.], Nagasaki University School of Medicine, Nagasaki 852-8501, and Division of Molecular and Clinical Microbiology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Medical Sciences, Nagasaki 852-8523 [M. O., S. Ko.], Japan

Purpose: Breast cancer resistance protein (BCRP/ABCG2), an ATP binding cassette half-transporter, confers resistance to mitoxantrone, doxorubicin, and topoisomerase I inhibitors of irinotecan and topotecan. Recently, we reported that BCRP efficiently transported SN-38 (the active metabolite of irinotecan) with a high affinity in lung cancer cells in vitro (K. Nakatomi et al., Biochem. Biophys. Res. Commun., 288: 827–832, 2001). The aim of this study is to explore the role of BCRP in the drug resistance of lung cancer.

Experimental Design: The BCRP mRNA expression in lung cancer cells and 23 untreated non-small cell lung cancer (NSCLC) tissues was quantitated by real-time reverse transcription-PCR. To evaluate the drug-efflux function of BCRP, the intracellular topotecan accumulation and drug sensitivity were measured in lung cancer cells with various levels of the BCRP mRNA expression by flow cytometric and tetrazolium dye assay, respectively.

Results: The levels of BCRP mRNA expression in the cell lines were significantly correlated with the BCRP function and the sensitivity to SN-38 and topotecan. In NSCLC tissues, the BCRP mRNA expression levels were widely dispersed. Five (22%) of 23 tissues expressed higher levels of the BCRP mRNA than that in NCI-H441 cells with active BCRP function conferring high resistance to topotecan in vitro.

Conclusions: Some NSCLC tissues expressed sufficient levels of the BCRP mRNA to confer drug resistance in vitro.

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