Chemoprotection against cyclophosphamide-induced urotoxicity: comparison of nine thiol protective agents.
Nine thiol chemoprotective compounds were compared for their abilities to reduce the urotoxicity induced by a high dose (1.5 mmol/kg i.p.) of the cancer chemotherapeutic agent, cyclophosphamide (CTX) in male Swiss-Webster mice. Toxicity was assessed by the change in body weight at 48 h, as well as the relative bladder weight (rbw), both a macroscopic and a microscopic rating of bladder damage, and the glutathione (GSH) status of the bladder and the liver. In addition, the rbw, macroscopic assessment, and GSH measurements were also carried out at 4 h, the point of maximal damage and GSH depletion. The powerful effects of compounds with the D-configuration indicated that direct action by the thiols is their most likely mechanism of action. Indirect action through GSH is unlikely because the D-amino acid cannot support GSH's biosynthesis.
Roberts
J C
JC
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
Francetic
D J
DJ
Zera
R T
RT
D000111:Acetylcysteine / Q000494:pharmacology; D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003545:Cysteine / Q000494:pharmacology / Q000031:analogs & derivatives; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D007536:Isomerism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D015080:Mesna / Q000494:pharmacology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology
D011355:Prodrugs; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D053778:Thiazolidines; C070066:2-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4-carboxylic acid; D003520:Cyclophosphamide; D005978:Glutathione; D003545:Cysteine; D004999:Amifostine; D015080:Mesna; D000111:Acetylcysteine