Failure of chronic glutathione elevation to reduce cytotoxicity produced by exposure to cis-diamminedichloroplatinum(II), ionizing radiation, or hyperthermia.
Chinese hamster ovary (CHO) cells cultured in vitro were continuously exposed to increasing concentrations of diethylmaleate (DEM). Chronic exposure of these cells (designated CHO/DEM) to 80 microM diethylmaleate resulted in an increase in cystine transport, a decrease in glutathione inhibition of the enzyme gamma-glutamylcysteine synthetase, elevation of intracellular glutathione levels to 4.3 times control, and elevation of glutathione-S-transferase activity by 6.6 times. Yet, CHO/DEM and control CHO cells exhibited the same ability to synthesize protein as measured by two-dimensional electrophoresis, the same cell cycle distribution, and the same population doubling times. CHO/DEM cells are resistant to DEM and diamide cytotoxicity, compared to control CHO cells. CHO/DEM cells were used to address the question of whether chronic elevation of glutathione, above control concentrations, reduced the cytotoxicity produced by exposure to cisplatin, gamma-radiation, or hyperthermia. The resulting dose-response curves obtained with CHO/DEM and control CHO cells indicated that chronic exposure to DEM, which resulted in chronic elevation of glutathione, did not provide protection against any of the three toxic treatments.
Freeman
M L
ML
Vanderbilt Center for Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Meredith
M J
MJ
Eisert
D R
DR
D000818:Animals; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D003553:Cystine / Q000378:metabolism; D005246:Feedback; D005260:Female; D005720:Gamma Rays; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006358:Hot Temperature; D007700:Kinetics; D008298:Maleates / Q000494:pharmacology*; D010053:Ovary; D014176:Protein Biosynthesis; D011506:Proteins / Q000302:isolation & purification
D008298:Maleates; D011506:Proteins; D003553:Cystine; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; C014476:diethyl maleate; D005978:Glutathione; D002945:Cisplatin