INFLUENCE OF TREATMENT WITH AMINOGLUTETHIMIDE ON PLASMA AND RED-BLOOD-CELL GLUTATHIONE STATUS IN BREAST-CANCER PATIENTS

Purpose: Elevated cellular glutathione has been associated with resist ance to cancer chemotherapy. Treatment with the aromatase inhibitor am inoglutethimide increases the concentration of gamma-glutamyl transpep tidase (gamma-GT) in breast cancer patients. This enzyme catalyzes the first step in the degradation of extracellular glutathione, and the p roducts forced may act as precursors for intracellular glutathione syn thesis, Methods: Plasma and red-blood-cell glutathione levels were det ermined in 26 patients suffering from advanced breast cancer before an d during treatment with aminoglutethimide (n = 16) or the steroidal ar omatase inhibitors exemestane or formestane (n = 10) and in 5 cancer p atients receiving dexamethasone. Results: Pretreatment values for gamm a-GT in the total patient group (n = 31) correlated negatively with th e level of reduced (P < 0.0001), oxidized (P < 0.025), and total gluta thione (P < 0.005) in plasma. Plasma gamma-GT levels increased by a me an value of 249% during treatment with aminoglutethimide. The concentr ation of reduced and oxidized glutathione in plasma decreased to 42.7% (P < 0.0005) and 80.6% (P < 0.005) of their pretreatment levels, resp ectively, This fall in reduced plasma glutathione correlated negativel y with the increase in gamma-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 gamma-GT (P < 0.005). Trea tment with the steroidal aromatase inhibitors (exemestane and formesta ne) or dexamethasone did not influence the plasma thiol status. Conclu sions: We conclude that aminoglutethimide influences plasma glutathion e disposition by mechanisms not related to estrogen suppression or due to glucocorticoids given in concert.