Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer.
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.
Oguri
T
T
Second Department of Internal Medicine, Hiroshima University Faculty of Medicine, Japan. oguri@mcai.med.hiroshima-u.ac.jp
Isobe
T
T
Suzuki
T
T
Nishio
K
K
Fujiwara
Y
Y
Katoh
O
O
Yamakido
M
M
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C120809:ABCC5 protein, human