Glutathione monoethyl ester can selectively protect liver from high dose BCNU or cyclophosphamide.
Normal Swiss Webster mice were treated with monocrotaline or high doses of three antitumor alkylating agents (BCNU, cyclophosphamide, or mitomycin C), all of which have been connected with hepatic veno-occlusive disease at our clinic. Prior administration of WR-2721 did not improve the survival of monocrotaline-treated animals. Glutathione (GSH) improved the survival of these animals to a small degree. Glutathione monoethyl ester (GSHet) almost completely protected animals from the toxicity of monocrotaline. Pretreatment with WR-2721 produced moderate increases in survival at the highest doses of BCNU, and at the lower BCNU doses none of the animals pretreated with WR-2721 died before they were killed on day 150. Pretreatment with GSHet gave good protection from BCNU toxicity at the highest dose of the drug, and there were no deaths in the groups of animals treated with GSHet 1 hour before BCNU. On a multiple dose schedule, GSH provided some protection from cyclophosphamide toxicity; GSHet gave a very good level of protection from cyclophosphamide. In none of these treatment groups were lesions suggestive of hepatic or pulmonary venoocclusive disease identified. In all three experimental protocols (monocrotaline, BCNU, and cyclophosphamide), there was a consistent decrease in hepatic toxicity after GSHet pretreatment; this was not observed in GSH- or WR-2721-pretreated animals. There was no evidence of protection of the FSaIIC fibrosarcoma growing in C3H mice as assayed by tumor growth delay or tumor cell survival in groups treated with two different doses of GSHet 1 hour before each drug injection compared to those treated with the BCNU or cyclophosphamide alone, or BCNU with cyclophosphamide. Pretreatment with GSHet did not alter the toxicity of these drugs to bone marrow. GSHet appears to be an effective protector of critical normal tissue and does not appear to protect tumor.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, MA 02115.
Crawford
J M
JM
Holden
S A
SA
Lin
Y
Y
Cathcart
K N
KN
Luchette
C A
CA
Flatow
J
J
D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D002330:Carmustine / Q000633:toxicity*; D002460:Cell Line; D003520:Cyclophosphamide / Q000633:toxicity*; D004347:Drug Interactions; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D016685:Mitomycin; D008937:Mitomycins / Q000633:toxicity; D016686:Monocrotaline; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity
D008937:Mitomycins; D011763:Pyrrolizidine Alkaloids; D016685:Mitomycin; D016686:Monocrotaline; C042431:S-ethyl glutathione; D003520:Cyclophosphamide; D005978:Glutathione; D004999:Amifostine; D002330:Carmustine