Oguri T, Isobe T, Suzuki T, Nishio K, Fujiwara Y, Katoh O, Yamakido M
Second Department of Internal Medicine, Hiroshima University Faculty of Medicine, Japan.
Int J Cancer. 2000 Apr 1;86(1):95-100. doi: 10.1002/(sici)1097-0215(20000401)86:1<95::aid-ijc15>3.0.co;2-g.
To investigate the role of the multidrug resistance-associated protein (MRP1) homologue MRP5 in relation to platinum drug resistance, we examined the steady-state levels of the mRNAs for MRP5 in both lung cancer cell lines and peripheral mononuclear cells (PMN) after exposure to platinum drug and in normal lung and lung cancer tissue specimens. Firstly, we examined MRP5 gene expression levels in 80 autopsy samples (40 primary tumors and 40 corresponding normal lung tissues) from 40 patients who had died from lung cancer. Next, we monitored MRP5 gene expression levels within 24 hr in both lung cancer cell lines incubated with cisplatin and in PMN from 10 previously untreated lung cancer patients after carboplatin administration alone. The MRP5 gene expression levels were assessed by quantitative reverse transcription polymerase chain reaction or RNase protection assay. The MRP5 expression levels in normal lung tissues and in tumors from patients exposed to platinum drugs during their lifetime were significantly higher than those in tissues from non-exposed patients. On the other hand, the MRP5 expression levels were not rapidly induced by platinum drugs either in lung cancer cell lines or in PMN within 24 hr. Our results suggest that increased expression levels of the MRP5 gene are associated with exposure to platinum drugs in lung cancer in vivo and/or the chronic stress response to xenobiotics.
为了研究多药耐药相关蛋白（MRP1）同源物MRP5在铂类药物耐药中的作用，我们检测了肺癌细胞系和外周血单个核细胞（PMN）在暴露于铂类药物后以及在正常肺组织和肺癌组织标本中MRP5 mRNA的稳态水平。首先，我们检测了40例死于肺癌患者的80份尸检样本（40个原发性肿瘤和40个相应的正常肺组织）中MRP5基因的表达水平。接下来，我们监测了顺铂处理的肺癌细胞系以及10例未经治疗的肺癌患者在单独给予卡铂后24小时内PMN中MRP5基因的表达水平。通过定量逆转录聚合酶链反应或核糖核酸酶保护试验评估MRP5基因的表达水平。在正常肺组织以及一生中暴露于铂类药物的患者肿瘤中，MRP5的表达水平显著高于未暴露患者的组织。另一方面，在肺癌细胞系或PMN中，铂类药物在24小时内并未迅速诱导MRP5的表达水平升高。我们的结果表明，MRP5基因表达水平的升高与体内肺癌患者暴露于铂类药物和/或对外源生物的慢性应激反应有关。
