Kubo H, Sumizawa T, Koga K, Nishiyama K, Takebayashi Y, Chuman Y, Furukawa T, Akiyama S, Ohi Y
Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Japan.
Int J Cancer. 1996 Dec 20;69(6):488-94. doi: 10.1002/(SICI)1097-0215(19961220)69:6<488::AID-IJC13>3.0.CO;2-Y.
The intrinsic or acquired resistance of urothelial cancer to chemotherapy is one major obstacle to successful treatment. Generally, the expression level of P-glycoprotein in urothelial cancer is low, so we accordingly investigated the expression of multidrug resistance-associated protein (MRP). We examined the expression of MRP mRNA by means of slot-blotting samples of 11 renal pelvic and/or ureteral tumors, 33 bladder tumors, one lung metastasis from a ureter tumor, 7 non-cancerous urothelia from patients with transitional-cell carcinoma (TCC) and one urothelium from a patient with renal-cell carcinoma (RCC). We also estimated, by Southern blotting, whether or not the MRP gene was amplified in clinical specimens that overexpressed MRP mRNA. MRP was detected immunohistochemically using a polyclonal antibody against MRP. In all, 5 of 11 renal pelvic and/or ureter tumors (45.5%), 17 of 33 bladder tumors (51.5%) and 4 of 7 non-cancerous urothelia of TCC patients (57.1%) expressed more than 2-fold the MRP mRNA levels of drug-sensitive human KB cells. There was no significant difference in the MRP mRNA level between primary and recurrent tumors. Low-grade urothelial carcinomas (G1 and G2 TCCs) expressed significantly higher levels of MRP mRNA than the high-grade G3 TCC. The MRP gene was not amplified in urothelial carcinomas, irrespective of their expression levels of MRP mRNA. Immunohistochemically, MRP was located mainly on the plasma membrane, but also detected on the cytoplasm of cancer cells. MRP may be one mechanism responsible for intrinsic drug resistance in low-grade urothelial cancer.
尿路上皮癌对化疗的内在或获得性耐药是成功治疗的一个主要障碍。一般来说，尿路上皮癌中P-糖蛋白的表达水平较低，因此我们相应地研究了多药耐药相关蛋白（MRP）的表达。我们通过斑点杂交检测了11例肾盂和/或输尿管肿瘤、33例膀胱肿瘤、1例输尿管肿瘤肺转移灶、7例移行细胞癌（TCC）患者的非癌性尿路上皮以及1例肾细胞癌（RCC）患者的尿路上皮中MRP mRNA的表达。我们还通过Southern杂交估计在MRP mRNA过表达的临床标本中MRP基因是否扩增。使用抗MRP的多克隆抗体通过免疫组织化学检测MRP。在11例肾盂和/或输尿管肿瘤中，有5例（45.5%）、33例膀胱肿瘤中有17例（51.5%）以及7例TCC患者的非癌性尿路上皮中有4例（57.1%）表达的MRP mRNA水平是药物敏感的人KB细胞的2倍以上。原发性肿瘤和复发性肿瘤之间的MRP mRNA水平没有显著差异。低级别尿路上皮癌（G1和G2 TCC）表达的MRP mRNA水平明显高于高级别G3 TCC。在尿路上皮癌中，无论其MRP mRNA表达水平如何，MRP基因均未扩增。免疫组织化学显示，MRP主要位于质膜上，但也在癌细胞的细胞质中检测到。MRP可能是低级别尿路上皮癌内在耐药的一种机制。
