Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance
Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance
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DOI：
10.1158/0008-5472.can-03-2417
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Kohno, S
中科院分区：
文献类型：
--
作者：
Nakamura, Y;Oka, M;Kohno, S
吉非替尼（“易瑞沙”，ZD1839）是一种口服活性、选择性表皮生长因子受体酪氨酸激酶抑制剂，单药治疗非小细胞肺癌临床有效。尽管吉非替尼联合各种细胞毒性药物已被报道在体外和小鼠模型中增强细胞毒性，但其机制仍未确定。为了探讨拓扑异构酶I抑制剂的作用机制，我们重点研究了乳腺癌耐药蛋白（BCRP/ABCG2）的外排泵，然后检测吉非替尼是否能恢复过表达BCRP的多药耐药癌细胞的药物敏感性。我们用伊立替康活性代谢物SN-38选择PC-6人小细胞肺癌细胞和多药耐药PC-6/SN2-5H细胞，用米托蒽醌和BCRP cDNA转染MCF-7/克隆8细胞选择过表达BCRP的MCF-7/MX细胞。采用四氮唑染色法检测抗肿瘤药物敏感性，FACScan检测细胞内拓扑替康积累量。利用PC-6/SN2-5H细胞的质膜囊泡进行拓扑替康转运研究。耐药PC-6/SN2-5H细胞过表达BCRP，但不表达表皮生长因子受体mRNA。10微摩尔吉非替尼逆转了拓扑替康、SN-38和米托蒽醌的耐药性，并增加了耐药细胞内拓扑替康的积累，但在亲代细胞中没有。此外，吉非替尼抑制拓扑替康向囊泡的转运，在Dixon图分析中，K-i值为1.01 +/- 0.09 mumol/L，表明吉非替尼对BCRP有直接抑制作用。然而，吉非替尼不能通过高效液相色谱法转运到囊泡中。这些结果表明，吉非替尼通过直接抑制而不是作为BCRP底物的竞争性抑制来逆转BCRP介导的耐药。吉非替尼联合拓扑异构酶I抑制剂治疗表达BCRP的肿瘤具有临床疗效。
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 K-i value was 1.01 +/- 0.09 mumol/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.