Cis-dichlorodiammineplatinum (II) (NSC-119875): hearing loss and other toxic effects in rhesus monkeys

Abstract

Ototoxicity and general toxicity of cis-dichlorodiammineplatinum (ii), a compound with antitumor activity, were evaluated in four rhesus monkeys. Audiometry was performed with shock avoidance to donditioned stimuli of pure tones at frequencies from 0.25 to 18 kHz. Histopathologic lesions of the inner ear were identified with phase-contrast microscopy of surface preparations from the organ of Corti. The monkeys were also submitted to physical examinations, hematologic and blood chemical determinations, necropsies, and histopathologic evaluations. Cis-dichlorodiammineplatinum (II) was injected intravenously in one monkey in five daily doses of 1.25 mg/kg (LD50) and in three monkeys in ten to 26 doses of 0.625 mg/kg five times per week. Transient hearing loss occurred in the monkey treated with the largest dose and in one of the three animals treated at the lower dose. In both monkeys apparently normal hearing reappeared after 120 and 200 days. No hearing loss was detectable in the other two animals. All four monkeys, however, had loss of hair cells in the organ of Corti and lesions were most severe among the outer hair cells of the lower turns. Other effects in all four monkeys included severe chronic glomerulonephritis with intermittent azotemia. Two monkeys (positive controls) injected intramuscularly with ten or 25 daily doses of neomycin sulfate (50 mg/kg) responded with delayed permanent hearing loss that appeared 3 months after the start of treatment. Deafness was substantiated by a total loss of inner hair cells in the upper turns, by a severe loss in the lower turns, and by a moderate or severe loss of outer hair cells in the lower turns. The above observations indicated that cis-dichlorodiammineplatinum (II), at a treatment regimen which caused more severe organ toxicity, caused less severe ototoxicity than neomycin sulfate and destroyed hair cells at different sites than neomycin sulfate.