Expression and functional analyses of breast cancer resistance protein in lung cancer.
OBJECTIVE
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.


METHODS
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.
Kawabata
Shigeru
S
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Oka
Mikio
M
Soda
Hiroshi
H
Shiozawa
Ken
K
Nakatomi
Katsumi
K
Tsurutani
Junji
J
Nakamura
Yoichi
Y
Doi
Seiji
S
Kitazaki
Takeshi
T
Sugahara
Kazuyuki
K
Yamada
Yasuaki
Y
Kamihira
Shimeru
S
Kohno
Shigeru
S
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019772:Topotecan / Q000494:pharmacology
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077146:Irinotecan; D019772:Topotecan; D008942:Mitoxantrone; D002166:Camptothecin