Relationship between expression of drug-resistance factors and drug sensitivity in normal human renal proximal tubular epithelial cells in comparison with renal cell carcinoma.
Relationship between expression of drug-resistance factors and drug sensitivity in normal human renal proximal tubular epithelial cells in comparison with renal cell carcinoma.
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DOI：
10.3892/or.14.3.601
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发表时间：
2005-09
期刊：
影响因子：
4.2
通讯作者：
T. Asakura;Akiko Imai;Noriko Ohkubo-Uraoka;Mayuko Kuroda;Yoko Iidaka;Kumiko Uchida;T. Shibasaki;K. Ohkawa
中科院分区：
文献类型：
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作者：
T. Asakura;Akiko Imai;Noriko Ohkubo-Uraoka;Mayuko Kuroda;Yoko Iidaka;Kumiko Uchida;T. Shibasaki;K. Ohkawa
本研究检测了人正常肾近端小管上皮细胞（RPTEC）和3种肾癌细胞（RCW、OS 2、TUHR 14 TKB）的耐药因子表达水平与其对抗癌药物敏感性的关系。RPTEC高表达P-糖蛋白（Pgp）、γ-谷氨酰半胱氨酸合成酶（gammaGCS）、顺铂（CDDP）耐药相关基因9（CRR 9），低表达空泡ATP酶（V-ATP酶），不表达多药耐药相关蛋白1（MRP 1）。14 TKB高表达γ GCS和CRR 9，低表达Pgp和V-ATPase，不表达MRP 1。OS 2高表达CRR 9，低表达Pgp、gammaGCS和MRP 1，不表达V-ATPase。RCW高表达Pgp、MRP 1和CRR 9，低表达γ GCS和V-ATPase。耐药因子的表达水平在细胞之间变化。各细胞GST活性与GST-pi表达水平相关，其中OS 2和RPTEC表达水平较高。96 h时测定抗癌药物对各细胞的细胞毒作用，RPTEC和RCW对顺铂和阿霉素（DXR）的敏感性低于其他细胞。用Pgp抑制剂维拉帕米治疗后，对DXR的敏感性增加，与Pgp表达水平成比例，用γ GCS抑制剂丁硫氨酸亚砜亚胺治疗后，对CDDP的敏感性增加，与γ GCS表达水平（对应于GSH含量）成比例。尽管用V-ATP酶抑制剂巴弗洛霉素处理RCC没有观察到对CDDP的敏感性显著增加，但巴弗洛霉素处理的细胞对DXR的敏感性增加约2倍。然而，药物敏感性和V-ATP酶的表达之间没有关系。RCC细胞系的特征（如抗性程度）不同，表现出许多抗性因子，或者相反，与正常细胞相比缺乏或具有降低的抗性因子。因此，在临床癌症化疗中有必要确定和测量各个肿瘤组织中各个抗性因子的表达水平。
The relationship between the expression level of putative drug resistance factors and sensitivity to anticancer drugs in human normal renal proximal tubule epithelial cells (RPTEC) and 3 kinds of renal cell carcinoma (RCC) cells, VMRC-RCW (RCW), OS-RC-2 (OS2), TUHR14TKB (14TKB), was examined. RPTEC exhibited high expression of P-glycoprotein (Pgp), gamma-glutamyl cysteine synthetase (gammaGCS) and cis-diamminedichloroplatinum (II) (CDDP) resistance-related gene 9 (CRR9), low expression of vacuolar ATPase (V-ATPase) and no expression of multidrug resistance-associated protein 1 (MRP1). 14TKB exhibited high expression of gammaGCS and CRR9, low expression of Pgp and V-ATPase, and no expression of MRP1. OS2 showed high expression of CRR9, low expression of Pgp, gammaGCS and MRP1, and no expression of V-ATPase. RCW exhibited high expression of Pgp, MRP1 and CRR9 and low expression of gammaGCS and V-ATPase. The level of expression of the resistance factors varied among the cells. GST activity and GST-pi expression level of each cell were correlated, and there were high levels in OS2 and RPTEC. When the cytotoxicity of anticancer drugs against each cell was measured at 96 h, the sensitivity to CDDP and Doxorubicin (DXR) in RPTEC and RCW was lower than that in the other cells. Sensitivity to DXR was enhanced by treatment with the Pgp inhibitor, Verapamil, in proportion to the Pgp expression level, and the sensitivity to CDDP was increased by the gammaGCS inhibitor, Buthionine sulfoximine, in proportion to the gammaGCS expression level (corresponding to GSH content). Although a significant increase in sensitivity to CDDP was not observed by treatment of RCC with the V-ATPase inhibitor, Bafilomycin, the sensitivity to DXR in Bafilomycin-treated cells increased about 2-fold. However, no relation between drug sensitivity and V-ATPase expression was observed. The features (such as degree of resistance) varied among the RCC cell lines manifesting many resistance factors or to the contrary, lacking or having lowered resistance factors in comparison with normal cells. Therefore, it is necessary in clinical cancer chemotherapy to determine and measure the level of expression of each resistance factor in respective tumor tissue.