Induction of gamma-glutamylcysteine synthetase gene expression by platinum drugs in peripheral mononuclear cells of lung cancer patients.
BACKGROUND
To investigate in vivo the roles of gamma-glutamylcysteine synthetase (gamma-GCS), multidrug resistance-associated protein (MRP), human canalicular multispecific organic anion transporter (cMOAT) and DNA topoisomerase I (topo I) in relation to platinum drug resistance, we monitored the changes of the steady-state levels of the mRNAs for these factors in peripheral mononuclear cells (PMN) after completing platinum drug administration.


METHODS
PMN from 46 subjects were studied. We obtained PMN from 14 previously untreated lung cancer patients and 14 normal volunteers to measure the baseline gene expression levels. We then obtained PMN from 18 patients with previously untreated advanced lung cancer before and after they received platinum drug treatment. We analyzed the gene expression levels by using the quantitative reverse transcription polymerase chain reaction (RT-PCR).


RESULTS
There were no differences in the baseline expression levels between normal volunteers and lung cancer patients in any of the genes. After platinum drug administration, the heavy subunit of gamma-GCS (gamma-GCSh) expression level increased 2.5-fold within 24 hours and the increase persisted for a month, whereas the light subunit of gamma-GCS (gamma-GCSl) expression level did not show an early response but had increased after a month. By contrast, the MRP, cMOAT and topo I expression levels were similar before, during and after chemotherapy.


CONCLUSIONS
These results suggest that the gene expression levels of both subunits of gamma-GCS play an important in vivo role in platinum drug resistance.
Oguri
T
T
Second Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
Fujiwara
Y
Y
Miyazaki
M
M
Takahashi
T
T
Kurata
T
T
Yokozaki
M
M
Ohashi
N
N
Isobe
T
T
Katoh
O
O
Yamakido
M
M
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D015152:Blotting, Northern; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016190:Carboplatin / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000187:drug effects*; D006801:Humans; D000077146:Irinotecan; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis*; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D005047:Etoposide; D000077146:Irinotecan; D016190:Carboplatin; D005721:Glutamate-Cysteine Ligase; D002945:Cisplatin; D002166:Camptothecin