Abstract
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.
Highlights
In this study, we examined the steady-state levels of mRNA for the y-glutamylcysteine synthetase (y-GCS), multidrug resistance-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) in human lung cancer specimens to elucidate their roles in relation to platinum drug resistance in vivo
Relationships between platinum drugs and patient characteristics y-GCS heavy subunit (y-GCSh), y-GCSI, MRP and cMOAT gene transcripts were detected in all the samples tested
There were no significant differences in ages, sex, smoking histories, histology, platinum doses received, intervals between the last platinum drug administration and death, or intervals from death to autopsy between each group
Summary
Seventy-six autopsy samples (38 primary tumours and their corresponding normal lung tissues) from 38 patients with lung cancer admitted to Hiroshima University and Chugoku Rousai General Hospitals from June 1992 to October 1996 were studied. Fresh specimens of primary lung tumours and normal lung tissues were obtained during autopsy after informed consent had been obtained. In order to examine gene induction in the human body after chemotherapy, peripheral mononuclear cells (PMN) were obtained from eight previously untreated lung cancer patients, who gave their informed consent. These patients were treated with cisplatin + irinotecan hydrochloride (CPT- 1 1), cisplatin + etoposide or carboplatin + etoposide. Five-millilitre heparinized blood samples were taken just before (0 h) and 6 and 24 h after completing platinum drug administration, and the PMN were separated immediately using lymphocyte preparation medium (Lymphoprep, Nycomed Pharma, Oslo, Norway), as described previously (Yao et al, 1993)
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