Modification of some of the toxic effects of daunomycin (NSC-82,151) by pretreatment with the antineoplastic agent ICRF 159 (NSC-129,943)

Abstract

Daunomycin (50 mg/kg) was lethal to Syrian golden hamsters ( 10 10 ) within 2–3 days, however, when this same dose was given 30 min after 100 mg/kg of 2,6-piperazinedione, 4,4′-propylenedi-, [±]-(ICRF 159) half of the animals ( 5 10 ) survived over 21 days. Between 40 and 51% of the total dose of daunomycin (50 mg/kg) could be recovered unchanged from hamster serum, urine, heart, lung, liver, kidney and spleen. The amount of unchanged daunomycin recovered from these tissues was higher (44–69%) in animals pretreated with ICRF 159. The amount of daunomycinone, a metabolite of daunomycin, recovered from the various tissues was less at all intervals in animals pretreated with ICRF 159 (0–3% of the total daunomycin dose) when compared with 4–9% recovered from the saline-pretreated hamsters. The iv administration of daunomycin (50 mg/kg) in the rhesus monkey produced hyperglycemia (140%) within 15 min, followed by a secondary hypoglycemia after 1–3 hr. Pretreatment with ICRF 159 (100 mg/kg) blocked the initial increase, but not the secondary decrease, in blood sugar over a 3-hr period. Daunomycin increased creatine phosphokinase and glutamic-oxaloacetic transaminase serum enzyme activities 13 and 4.5 times, respectively. Smaller increases were detected in serum enzyme activities of glutamic-pyruvic transaminase (3.5 times) and lactic acid dehydrogenase (2.5 times). The increases in serum enzyme activities were attenuated in animals pretreated with ICRF 159. In the present experiments, a decrease in production of daunomycinone may be an important factor in the reduction of daunomycin toxicity.