Cis-Dichlorodiammineplatinum(II) (NSC-119 875): Preclinical toxicologic evaluation of intravenous injection in dogs, monkeys and mice

Abstract

cis-Dichlorodiammineplatinum(II), a compound with antineoplastic and antimitotic activity, which inhibited the synthesis of DNA and to a lesser extent of RNA and proteins, was submitted to a preclinical pharmacologic evaluation in 16 dogs, 10 monkeys, and 120 mice. The LD50 following a single dose iv in Swiss mice was 13.4 mg/kg for males and 12.32 mg/kg for females. The minimum lethal dose for the dog was a single iv injection of 2.5 mg/kg or 5 daily consecutive injections of 0.75 mg/kg and for the monkey, 5 daily doses of 2.5 mg/kg. The treatment elicited severe morbidity within 5–17 days and the time of onset was dose related. Toxic signs included severe hemorrhagic enterocolitis, severe hypocellularity of the bone marrow and lymphoid tissues and marked renal lesions (renal tubular necrosis in the dog and nephrosis in the monkey). Dogs also showed occasional pancreatitis and monkeys myocarditis and occasional degeneration of the spermatogenic cells. Renal lesions were the most severe toxic changes in survivors and were manifested by azotemia, hypochloremia, proteinuria, appearance of urinary erythrocytes, leukocytes and decreased 24-hr excretion of lactate dehydrogenase in dogs and by protracted polyuria in monkeys. Occasional hypocalcemia also occurred. In dogs and monkeys that survived the treatment, toxicity regressed entirely within 55–124 days. Treatment affected primarily tissues with a high rate of cell division (intestines, bone marrow, lymphoid tissues and occasionally testes) and tissues known for primary excretion of the compound (intestines and kidneys).