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.