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 t o platinum drug resistance in vivo. Seventy-six autopsy samples (38 pr imary tumours and their corresponding normal lung tissues) obtained fr om 38 patients were analysed using the quantitative reverse transcript ion polymerase chain reaction (RT-PCR) method. Both subunits (heavy an d light subunits) of gamma-GCS expression levels of normal lung and tu mour tissues exposed to platinum drugs during life were significantly higher than those of non-exposed tissues, whereas only the MRP express ion levels of tumours were elevated in association with ante-mortem pl atinum drug exposure. The gamma-GCS and MRP expression levels correlat ed significantly. The cMOAT expression levels did not correlate with a nte-mortem platinum drug exposure. Next, we monitored gamma-GCS heavy subunit expression levels in peripheral mononuclear cells of eight pre viously untreated lung cancer patients after platinum drug administrat ion, which revealed that these drugs induced gamma-GCS expression in v ivo. These results suggest that gamma-GCS expression is induced by pla tinum drugs in vivo and/or the physiological stress response to xenobi otics.