RT Journal Article
SR Electronic
T1 Gefitinib (“Iressa”, ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses Breast Cancer Resistance Protein/ABCG2–Mediated Drug Resistance
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 1541
OP 1546
DO 10.1158/0008-5472.CAN-03-2417
VO 65
IS 4
A1 Nakamura, Yoichi
A1 Oka, Mikio
A1 Soda, Hiroshi
A1 Shiozawa, Ken
A1 Yoshikawa, Megumi
A1 Itoh, Akiko
A1 Ikegami, Yoji
A1 Tsurutani, Junji
A1 Nakatomi, Katsumi
A1 Kitazaki, Takeshi
A1 Doi, Seiji
A1 Yoshida, Hisahiro
A1 Kohno, Shigeru
YR 2005
UL http://cancerres.aacrjournals.org/content/65/4/1541.abstract
AB Gefitinib (“Iressa”, ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non–small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan, SN-38, and mitoxantrone resistance, and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells. Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the Ki value was 1.01 ± 0.09 μmol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP. ©2005 American Association for Cancer Research.