title: Acceleration of cisplatin ototoxicity by perilymphatic application of 4-methylthiobenzoic acid.
abstract: The antitumor agent cisplatin has dose-limiting side effects such as ototoxicity. Systemical co-treatment with anti-oxidants like 4-methylthiobenzoic acid (MTBA) and sodium thiosulfate (STS) provides protection against cisplatin ototoxicity. However, systemically administered protective agents may reduce the chemotherapeutic effect of cisplatin. Local application of the protective agents could avoid this undesirable effect. In the present study, we aimed at suppressing cisplatin-induced ototoxicity in guinea pigs by administering MTBA or STS perilymphatically through cochlear perfusion. Guinea pig cochleas were perfused for 10 min with artificial perilymph (ArtP) containing cisplatin at 0.3 mg/ml, either alone, or in combination with MTBA (0.1 or 1.0 mg/ml) or STS (0.75 or 3.0 mg/ml). The compound action potential (CAP) and the summating potential (SP), evoked by 8 kHz tone bursts, and the endocochlear potential (EP; MTBA only) were measured just before and 1, 2, 3 and 4 h after perfusion. Cisplatin gradually reduced the CAP amplitude in time. Adding MTBA only accelerated this ototoxic effect. After cisplatin treatment a decline was found in the EP, irrespective of co-treatment, i.e., addition of MTBA did not accelerate the EP decrease. In contrast to MTBA, STS ameliorated the ototoxic effect of cisplatin. In conclusion, local application of anti-oxidants can ameliorate cisplatin ototoxicity but this is not a feature of all anti-oxidants.
authors.affiliation: Hearing Research Laboratories, Department of Otorhinolaryngology, University Medical Center Utrecht, Room G02.531, P.O.Box 85.500, NL-3508 GA, The Netherlands.
authors.forename: Natalie L M
authors.initials: NL
authors.lastname: Cappaert
authors.forename: Sjaak F L
authors.initials: SF
authors.lastname: Klis
authors.forename: Jeroen
authors.initials: J
authors.lastname: Wijbenga
authors.forename: Guido F
authors.initials: GF
authors.lastname: Smoorenburg
mesh_terms: D000161:Acoustic Stimulation; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000506:poisoning*; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology; D002945:Cisplatin / Q000506:poisoning*; D003051:Cochlea / Q000187:drug effects* / Q000502:physiology*; D004338:Drug Combinations; D004357:Drug Synergism; D004594:Electrophysiology; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D010477:Perfusion; D010498:Perilymph; D013885:Thiosulfates / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
chemical_list: C104409:4-methylthiobenzoic acid; D000970:Antineoplastic Agents; D000975:Antioxidants; D001565:Benzoates; D004338:Drug Combinations; D013885:Thiosulfates; C017717:sodium thiosulfate; D002945:Cisplatin