title: Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity.
abstract: Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The impact of STS was evaluated by measuring the onset of growth of LX-1 human small cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was a decrease in the time to tumor progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.
authors.affiliation: Department of Neurology, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Muldoon
authors.forename: M A
authors.initials: MA
authors.lastname: Pagel
authors.forename: R A
authors.initials: RA
authors.lastname: Kroll
authors.forename: R E
authors.initials: RE
authors.lastname: Brummett
authors.forename: N D
authors.initials: ND
authors.lastname: Doolittle
authors.forename: E G
authors.initials: EG
authors.lastname: Zuhowski
authors.forename: M J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: E A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use*; D001309:Auditory Threshold / Q000187:drug effects*; D016190:Carboplatin / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000633:toxicity*; D004334:Drug Administration Schedule; D004432:Ear, Middle / Q000187:drug effects / Q000473:pathology; D005047:Etoposide / Q000633:toxicity; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D011923:Rats, Nude; D013885:Thiosulfates / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000931:Antidotes; D013885:Thiosulfates; D005047:Etoposide; D016190:Carboplatin; C017717:sodium thiosulfate; D002945:Cisplatin