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Failure of Chronic Glutathione Elevation to Reduce Cytotoxicity Produced by Exposure to cis-Diamminedichloroplatinum(II), Ionizing Radiation, or Hyperthermia¹

Vanderbilt Center for Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [M. L. F., D. R. E.], and Department of Biochemistry, School of Dentistry, Oregon Health Sciences University, Portland Oregon 97201 [M. J. M.]

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 µM diethylmaleate resulted in an increase in cystine transport, a decrease in glutathione inhibition of the enzyme -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, -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.

¹ Supported in part by USPHS Grants CA 38079 and ES 03272 and pilot project support from ES 00267.

² To whom requests for reprints should be addressed.

Received 10/19/89. Revised 3/13/90.