Severe generalized glutathione reductase deficiency after antitumor chemotherapy with BCNU" [1,3-bis(chloroethyl)-1-nitrosourea].
Patients receiving BCNU [1,3-bis(2 chloroethyl)-1-nitrosourea] acquire a profound deficiency of erythrocytic oxidized glutathione reductase (GSSG-R) within minutes after the first intravenous injection of a single therapeutic dose (75 mg/M.2) of the drug. This effect is not accompanied by changes in the activites of 19 additional erythrocytic enzymes tested, is reproducible in vitro in a dose-related manner, and is not caused by the antitumor agents administered concurrently with the nitrosourea. The inactivation of erythrocytic GSSG-R results in decreased levels of reduced glutathione (GSH), marked GSH instability and disturbed hydrogen peroxide removal with a positibe ascorbate cyanide test and leads to increased susceptibility to oxidative hemolysis, particularly in glucose-6-phosphate dehydrogenase (G-6-D)-deficient patients. BCNU inhibits GSSG-R irreversibly, probably through alkylation rather than carbamylation, and the reappearance of enzyme activity in vivo after each chemotherapy pulse depends on the capacity of the marrow to release erythrocytes with normal activity formed during the drug-free interval. BCNU inhibits GSSG-R not only in erythrocytes but also in human leukocytes and platelets, as well as in yeast, monkey erythrocytes, and all the organs tested in the mouse. This generalized, severe, and specific GSSG-R deficiency caused by therapeutic doses of BCNU may enhance or mediate the toxic and antitumor effects of the nitrosourea and provides a simple yet sensitive biochemical means of monitoring bone marrow reserve in patients receiving multiple courses of chemotherapy with this agent.
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D002330:Carmustine / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D005980:Glutathione Reductase / Q000172:deficiency*; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy
D005980:Glutathione Reductase; D001205:Ascorbic Acid; D002330:Carmustine