title: A low-dose regimen of cisplatin before high-dose cisplatin potentiates ototoxicity.
abstract: OBJECTIVE
  Cochlear preconditioning with low doses of kanamycin or noise can reduce susceptibility to noise- and ototoxic drug-induced hearing loss. The current study was undertaken to investigate whether a preconditioning regimen of low-dose cisplatin would alter susceptibility to ototoxicity induced by a single large dose of cisplatin.
  
  
  METHODS
  In vivo study using an animal model.
  
  
  METHODS
  Twenty-six Fischer 344/NHsd rats were used in the study. The low-dose regimen consisted of cisplatin (2 or 3 mg/kg) given every 2 weeks by intraperitoneal injection. Control animals received injections of saline on the same schedule as the cisplatin injections. Four injections were done in total. Following the preconditioning interval, seven of the animals were sacrificed for hair cell analyses. The remaining 19 animals were exposed to 12 mg/kg cisplatin by intraperitoneal infusion to induce cochlear injury. Auditory brainstem response (ABR) thresholds were measured 3 days after cisplatin, and the cochleae from the 19 animals were harvested and analyzed.
  
  
  RESULTS
  Statistical analyses revealed no threshold shifts, but mild outer hair cell losses, after the low-dose regimen. ABR threshold shifts in the rats exposed to the 12 mg/kg cisplatin dose were significantly higher at day 3 in the animals that underwent preconditioning with low-dose cisplatin. Outer hair cell losses were also greater in the preconditioned animals.
  
  
  CONCLUSIONS
  Preconditioning with low-dose cisplatin, using the protocol applied in the current experiment, created potentiation of cisplatin ototoxicity, rather than protection from it. There are numerous possible explanations for this effect that should be considered.
  
  
  METHODS
  NA.
authors.affiliation: Department of Speech and Hearing Science, The Ohio State University, Columbus, Ohio, U.S.A.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Harrison
authors.forename: J Riley
authors.initials: JR
authors.lastname: DeBacker
authors.forename: Eric C
authors.initials: EC
authors.lastname: Bielefeld
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced*; D007274:Injections, Intraperitoneal; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002945:Cisplatin
keywords: Cisplatin; Fischer 344; auditory brainstem response; preconditioning