SEVERE GENERALIZED GLUTATHIONE REDUCTASE DEFICIENCY AFTER ANTITUMOR CHEMOTHERAPY WITH BCNU [1,3-BIS(CHLOROETHYL)-1-NITROSOUREA]
- 1 January 1977
- journal article
- research article
- Vol. 89 (5), 1080-1091
Abstract
Patients receiving BCNU acquire a profound deficiency of erythrocytic oxidized glutathione reductase (GSSG-R) within minutes after the 1st i.v. injection of a single therapeutic dose (75 mg/m2) of the drug. This effect is not accompanied by changes in the activities of 19 additional erythrocytic enzymes tested, is reproducible in vitro in a dose related manner and is not caused by 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 positive ascorbate cyanide test and leads to increased susceptibility to oxidative hemolysis, particularly in glucose-6-phosphate dehydrogenase (G-6-PD) 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 leukocytes and platelets, as well as in yeast, monkey erythrocytes and all 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.This publication has 12 references indexed in Scilit:
- Population, Family and Biochemical Investigation of Human Adenylate Kinase PolymorphismNature, 1967
- Hereditary Hemolytic Anemia with Hexokinase DeficiencyNew England Journal of Medicine, 1967
- Effects of Glucose-6-Phosphate Dehydrogenase Deficiency Upon the Host and Upon Host-Drug-Malaria Parasite InteractionsMilitary Medicine, 1966
- A Simple Visual Screening Test for Glucose-6-Phosphate Dehydrogenase Deficiency Employing Ascorbate and CyanideNew England Journal of Medicine, 1966
- Studies on Chromated Erythrocytes. Effect of Sodium Chromate on Erythrocyte Glutathione Reductase*JCI Insight, 1964
- Glutathione Peroxidase: The Primary Agent for the Elimination of Hydrogen Peroxide in Erythrocytes*Biochemistry, 1963
- STUDIES OF THE METABOLISM OF HUMAN ERYTHROCYTE MEMBRANES*JCI Insight, 1963
- IMPROVED METHOD FOR DETERMINATION OF BLOOD GLUTATHIONE1963
- Pyruvate Kinase (PK) Deficiency Hereditary Nonspherocytic Hemolytic AnemiaBlood, 1962
- PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENTJournal of Biological Chemistry, 1951