Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity

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 chemoprotectiv e 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 r educes 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 ef ficacy of carboplatin, The impact of STS was evaluated by measuring the ons et 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 treatm ent with carboplatin and etoposide, there was a decrease in the time to tum or progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytoto xicity of the chemotherapy. STS infusion did not significantly affect ultra filterable platinum pharmacokinetics in the guinea pig. To explore the pote ntial wider applicability of STS, in a pilot study we tested its efficacy a gainst cisplatin ototoxicity, Delayed administration of STS, 2 h after cisp latin, was protective against cisplatin-induced oto-toxicity 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 mec hanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy .