Expression of gamma-glutamylcysteine synthetase (gamma-GCS) and multidrug resistance-associated protein (MRP), but not human canalicular multispecific organic anion transporter (cMOAT), genes correlates with exposure of human lung cancers to platinum drugs.
We examined the steady-state levels of mRNA for gamma-glutamylcysteine synthetase (gamma-GCS), multidrug resistance-associated protein (MRP) and human canalicular multispecific organic anion transporter (cMOAT) in human lung cancer specimens to elucidate their roles in relation to platinum drug resistance in vivo. Seventy-six autopsy samples (38 primary tumours and their corresponding normal lung tissues) obtained from 38 patients were analysed using the quantitative reverse transcription polymerase chain reaction (RT-PCR) method. Both subunits (heavy and light subunits) of gamma-GCS expression levels of normal lung and tumour tissues exposed to platinum drugs during life were significantly higher than those of non-exposed tissues, whereas only the MRP expression levels of tumours were elevated in association with ante-mortem platinum drug exposure. The gamma-GCS and MRP expression levels correlated significantly. The cMOAT expression levels did not correlate with ante-mortem platinum drug exposure. Next, we monitored gamma-GCS heavy subunit expression levels in peripheral mononuclear cells of eight previously untreated lung cancer patients after platinum drug administration, which revealed that these drugs induced gamma-GCS expression in vivo. These results suggest that gamma-GCS expression is induced by platinum drugs in vivo and/or the physiological stress response to xenobiotics.
Oguri
T
T
Second Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
Fujiwara
Y
Y
Isobe
T
T
Katoh
O
O
Watanabe
H
H
Yamakido
M
M
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D002945:Cisplatin; D004264:DNA Topoisomerases, Type I; D005721:Glutamate-Cysteine Ligase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger