Influence of treatment with aminoglutethimide on plasma and red-blood-cell glutathione status in breast cancer patients

Abstract

Purpose: Elevated cellular glutathione has been associated with resistance to cancer chemotherapy. Treatment with the aromatase inhibitor aminoglutethimide increases the concentration of γ-glutamyl transpeptidase (γ-GT) in breast cancer patients. This enzyme catalyzes the first step in the degradation of extracellular glutathione, and the products formed may act as precursors for intracellular glutathione synthesis. Methods: Plasma and red-blood-cell glutathione levels were determined in 26 patients suffering from advanced breast cancer before and during treatment with aminoglutethimide (n=16) or the steroidal aromatase inhibitors exemestane or formestane (n=10) and in 5 cancer patients receiving dexamethasone. Results: Pretreatment values for γ-GT in the total patient group (n=31) correlated negatively with the level of reduced (P<0.0001), oxidized (P<0.025), and total glutathione (P<0.005) in plasma. Plasma γ-GT levels increased by a mean value of 249% during treatment with aminoglutethimide. The concentration of reduced and oxidized glutathione in plasma decreased to 42.7% (P<0.0005) and 80.6% (P < 0.005) of their pretreatment levels, respectively. This fall in reduced plasma glutathione correlated negatively with the increase in -GT (P<0.001). The ratio of oxidized to reduced glutathione increased by 88.9% (P<0.005), and this increase correlated positively with the increase in γ-GT (P<0.005). Treatment with the steroidal aromatase inhibitors (exemestane and formestane) or dexamethasone did not influence the plasma thiol status. Conclusions: We conclude that aminoglutethimide influences plasma glutathione disposition by mechanisms not related to estrogen suppression or due to glucocorticoids given in concert.