PROTECTIVE EFFECTS OF A NEUROTROPHIC ACTH((4-9)) ANALOG ON CISPLATIN OTOTOXICITY IN RELATION TO THE CISPLATIN DOSE - AN ELECTROCOCHLEOGRAPHIC STUDY IN ALBINO GUINEA-PIGS

Cisplatin is a potent cell cycle non-specific chemotherapeutic agent t hat produces side effects including high-frequency hearing loss. Hamer s et al. (1994) studied electrophysiologically the effect of an ACTH(( 4-9)) analog, also known as ORG2766, on the ototoxicity of cisplatin ( administered at 2 mg/kg/day for 8 days) in guinea pigs. ORG2766 was gi ven concomitantly with cisplatin during the 8 day period and an additi onal dose was given on day 9. The conclusion of this study was that OR G2766 might partially prevent cisplatin ototoxicity, but that the chos en cisplatin dose (2 mg/kg/day; 8 days) might have been too high. Beca use of the high cisplatin dose the protective power of the co-treatmen t with ORG2766 might not have stretched to all animals. In this study the results of co-treatment with the same dose and daily schedule of O RG2766 and cisplatin doses of 1.0 mg/kg/day and 1.5 mg/kg/day for 8 da ys are presented. The measurements were performed over a broad range o f frequencies (0.5-16 kHz). Electrocochleography was performed at day 10. In the 1.0 mg/kg/day group there was no beneficial effect of ORG27 66, although a tendency towards a division between a subgroup resembli ng control animals and a subgroup with severe cisplatin effects was no ted in the co-treated group. In the 1.5 mg/kg/day co-treated group thr ee animals showed compound action potential (CAP) amplitudes close to those of the controls at all frequencies except the very highest (12 a nd 16 kHz), the remaining three had CAP amplitudes comparable to those of animals in the cisplatin alone group. The effect of ORG2766 on the latter group of six animals taken together was statistically signific ant. The dichotomy in the results for the 1.5 mg/kg/day group co-treat ed with ORG2766 suggests that ORG2766 may have a protective effect aga inst cisplatin ototoxicity which, however, depends on a factor current ly unknown. (C) 1998 Elsevier Science B.V. All rights reserved.