Gefitinib (“Iressa”, ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses Breast Cancer Resistance Protein/ABCG2–Mediated Drug Resistance

Abstract

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 BCRPoverexpressing 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 K i value was 1.01 F 0.09 Mmol/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. (Cancer Res 2005; 65(4): 1541-6)

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

“…Overexpression of EGF and its receptor is present in patients with osteosarcoma [5,28,65] and causes continuous growth and antiapoptosis signals in osteosarcoma cells [5,28,29]. Additionally, EGF stimulates motility [32,64], invasion, and tumor progression of other types of cancer cells [44,46]. Our results further support the development of EGF-R inhibitors as a novel osteosarcoma therapy.…”

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

“…Elkind et al (2005) showed that low concentrations of gefitinib (o1 mM) significantly activated BCRP-ATPase activity in isolated membranes of BCRP-expressing mammalian MCF-7/MX and A431 cells, whereas higher concentrations (41 mM) had a markedly lower stimulatory effect. Consequently, this might explain the lack of gefitinib transport into vesicles of PC-6/SN2-5H cells, since a gefitinib concentration of 30 mM was used in this study (Nakamura et al, 2005). These results suggest that, as discussed above for imatinib, gefitinib might also have a narrow window, especially in a low concentration range, where its active transport by BCRP is efficient.…”

“…Contradictory data have been published also for the epidermal growth factor receptor (EGFR) TKI gefitinib, since some authors describe it as a BCRP substrate, while others classified it as an inhibitor and not a substrate (Elkind et al, 2005;Nakamura et al, 2005). Most likely, the apparent discrepancy in these results is due to the selected concentrations of gefitinib used in the different studies.…”

“…This suggests that BCRP prevents the action of gefitinib by effluxing this compound from the cell before it can interact with plasma membrane-associated EGFR. Similar to canertinib and imatinib, gefitinib is also a BCRP inhibitor and reverses BCRP-mediated drug resistance both in vitro and in vivo (Yanase et al, 2004;Nakamura et al, 2005).…”

A Review of an Unfavorable Subset of Breast Cancer: Estrogen Receptor Positive Progesterone Receptor Negative

“…EGF receptor (EGFR) family members are expressed in both normal and malignant breast epithelial cells, and their overexpression in breast cancer is predictive of a poor prognosis. EGFR promotes tumor progression, including invasion, angiogenesis, metastasis, and resistance to treatment, by blocking apoptosis [1]. Crosstalk between EGFR and ovarian steroid hormone receptors continues in breast cancer cells [2].…”