Ototoxicity of cis-dichlorodiammine platinum (II) in the guinea pig

Abstract

cis-Dichlorodiammine platinum (II) (NSC-119 875), an agent with potent antineoplastic activity which also induces renal, intestinal, and bone marrow toxicity, was tested for ototoxic effects in guinea pigs. Ototoxicity was evaluated by the disappearance of Preyer's reflex in response to pure tones of 5, 7, and 10 kHz and by histopathological evaluation of the inner ear with surface preparations or midmodiolar sections. Groups of five guinea pigs treated with 8–40 ip injections of cis-dichlorodiammine platinum (II) 1 mg/kg (5 doses/wk) or with 10–15 doses of 1.5 mg/kg developed permanent deafness and histopathological lesions with pronounced loss of outer hair cells in the lower turns of the organ of Corti. Frequently, entire rows of outer hair cells disappeared and only a few isolated hair cells remained intact. Moderate numbers of outer pillar cells were missing and occasional inner hair cells and pillar cells were also damaged. Hair cell lesions included degeneration, complete cytolysis, and replacement by phalangeal scars. Single doses of 6, 9, 12, or 18 mg/kg of cis-dichlorodiammine platinum (II) produced permanent hearing loss as early as Day 3 and a scattered pattern of outer hair cell loss on Day 4 with cytological changes similar to but less severe than those observed for multiple doses. Neomycin sulfate-treated guinea pigs used as positive controls (eight consecutive daily doses of 150–250 mg/kg) showed a similar pattern of hair cell loss as produced by cis-dichlorodiammine platinum (II). Positive controls treated with a single dose of 6-aminonicotinamide from 2.5 to 20 mg/kg, developed severe damage to both inner and outer hair cells, pillar cells, and spiral ganglia. Occasional strial atrophy was also observed.