Expression of drug-resistant factor in renal cell cartinoma and overcoming the drug-resistance by treatment with a conjugate of doxorubicin with glutathion

本文研究了正常人肾近端小管上皮细胞（RPTEC）和肾癌细胞（RCC）的耐药因子（Pgp/MRP 1/γGCS/V-ATPase/CRR 9）的表达及对抗癌药物的敏感性。与RPTEC相比，RCW中Pgp、γGCS和CRR 9表达增强，OS 2中Pgp、MRP 1和CRR 9表达增强，14 TKB中Pgp、MRP 1和CRR 9表达增强。各细胞GST活性与GST-Ⅱ表达量呈正相关（OS 2>RPTEC>>RCW= 14 TKB =0）。CDDP和DXR对RCC的细胞毒作用低于RPTEC，对RCW的细胞毒作用最低。对顺铂和地塞米松的耐药依赖于耐药因子的表达，而GSH-DXR的细胞毒作用与耐药因子的表达无关。GST-Ⅱ正、反义cDNA转染细胞后，GST-Ⅱ表达增强或抑制，表明GSH-DXR对CDDP和DXR的耐药性与GST-Ⅱ表达增强或抑制有关，但GSH-DXR对GST-Ⅱ转染细胞的细胞毒作用无明显变化。从活性中心（W38 H或C47 S）突变的GST-Ⅱ对转染子的细胞毒性结果来看，GST-Ⅱ分子的活性中心是GST-Ⅱ产生耐药性所必需的。

Expression of some drug resistant factors (Pgp/MRPl/γGCS/V-ATPase/CRR9) and sensitivity of anticancer drugs against normal human renal proximal tubule epithelial cells (RPTEC) and some renal cancer cells (RCC) were studied. Overexpression of Pgp, γGCS and CRR9 in RCW, Pgp, MRP1 and CRR9 in OS2, Pgp, MRPl and CRR9 in 14TKB were observed in comparison with those in RPTEC. GST activity in each cells was corresponded to GST-_II expression (OS2>RPTEC>>RCW=14TKB=0). Cytotoxicity of CDDP and DXR against RCC was lowered than that against RPTEC and that against RCW was lowest in RCC. The resistance to CDDP an DXR was dependent on the expression of the factors but cytotoxicity of GSH-DXR exhibited potently withoulj the expression of drug resistant factors. Enhancement and suppression of GST-_II expression by transfection of GST-_II sense and antisense cDNA into the cells showed the relation of drug resistance to CDDP and DXR but little change in cytotoxicity of GSH-DXR against GST-_II transfectant was observed. From the result in cytotoxicity against transfectant of site-directedly mutated GST-n which mutated in active center (W38H or C47S), the active Center of GST-_II molecule was necessary to exhibit the drug-resistance by GST-_II.