Influence of treatment with aminoglutethimide on plasma and red-blood-cell glutathione status in breast cancer patients.
OBJECTIVE
Elevated cellular glutathione has been associated with resistance to cancer chemotherapy. Treatment with the aromatase inhibitor aminoglutethimide increases the concentration of gamma-glutamyl transpeptidase (gamma-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 gamma-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 gamma-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 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). 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.
Berntsen
H
H
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Lønning
P E
PE
Ekse
D
D
Netteland
B
B
Johannessen
D C
DC
Berge
R
R
Svardal
A
A
D000368:Aged; D000616:Aminoglutethimide / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D003907:Dexamethasone / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005978:Glutathione / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D005723:gamma-Glutamyltransferase / Q000097:blood
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D000616:Aminoglutethimide; D003907:Dexamethasone; D005723:gamma-Glutamyltransferase; D005978:Glutathione