Effect of Buthionine Sulfoximine (NSC-326231) on Melphalan (NSC-8806)-Induced Toxicity in Dogs

摘要

The study was designed to examine the effects of BSO-pretreatment (which depletes tissue levels of glutathione) on Melphalan-induced toxicity in beagle dogs. Doses of BSO (800 mg/kg/dose) administered orally every 12 hours for a total of 4 doses to dogs produced evidence of severe toxicity in the CNS (hyperactivity, agressiveness, and convulsions), GI tract (emesis and diarrhea) and immune system (lymphoid depletion). Due to overt BSO-induced toxicity and humane concern for the animals, the study was terminated prior to the scheduled treatment with Melphalan on Study Day 3. Four of the twelve BSO-treated dogs continued to have intermittent seizures, approximately 36 hours after the last BSO dose was administered. The dogs were considered to be moribund and were sacrificed on Study Day 4. No drug-related gross lesions were observed during the necropsy. Microscopic evaluation of the collected tissues indicated that there was mild to marked, drug-related thymic necrosis and lymphoid depletion in several tissues that was considered secondary to convulsive episodes.