Histological effects of co-administration of an ACTH((4-9)) analogue, ORG 2766, on cisplatin ototoxicity in the albino guinea pig

Cisplatin is one of the most potent antineoplastic drugs presently known, b ut its therapeutic efficacy is seriously limited by several side effects su ch as ototoxicity. Several compounds that are known for their nephroprotect ive effects also seem to reduce the incidence and severity of cisplatin-ind uced ototoxicity. Hamers et al. (1994) and De Groot et al. (1997) investiga ted the possibly protective effect of concomitant administration of the ACT H((4-9)) analogue ORG 2766 upon cisplatin ototoxicity in guinea pigs. Anima ls were treated with cisplatin at a daily dose of 2.0 mg/kg for 8 consecuti ve days and ORG 2766 at a daily dose of 75 mu g/kg for 9 days. Concomitant administration of cisplatin plus ORG 2766 resulted in a bimodal distributio n of the electrophysiological data (compound action potential and cochlear microphonics amplitudes) and the histological data (outer hair cell (OHC) c ounts). It was surmised that this dichotomy might occur at a certain cispla tin dose. We investigated whether this protective effect of ORG 2766 could be enhanced by reducing the daily dose of cisplatin while maintaining the s ame dose of ORG 2766. Thirty-six animals were treated with daily i.p. injec tions of cisplatin at a dose of 1.0 mg/kg (n = 18) or 1.5 mg/kg (n = 18) fo r 8 consecutive days. When comparing the mean OHC counts of the different e xperimental groups, treatment with cisplatin at a daily dose of 1.5 mg/kg f or 8 consecutive days resulted in a considerable loss of OHCs, which was si gnificantly reduced after co-administration of ORG 2766. Co-treatment with ORG 2766 did not result in a change in the volume of the scala media. The p resent results are in agreement with the electrophysiological results publi shed earlier (Stengs et al., 1998b). (C) 2000 Elsevier Science B.V. All rig hts reserved.