Delayed Administration of Sodium Thiosulfate in Animal Models Reduces Platinum Ototoxicity without Reduction of Antitumor Activity

Delayed Administration of Sodium Thiosulfate in Animal Models Reduces Platinum Ototoxicity without Reduction of Antitumor Activity1

Departments of Neurology [L. L. M., R. A. K., N. D. D., E. A. N.], Biochemistry and Molecular Biology [E. A. N.], Pharmacology [R. E. B.], and Cell and Developmental Biology [L. L. M.], and Division of Neurosurgery [E. A. N.], Oregon Health Sciences University, Portland, Oregon 97201; Department of Otolaryngology, Oregon Hearing Research Center, Portland, Oregon 97201 [R. E. B.]; Veterans Administration Medical Center, Portland Oregon 97201 [E. A. N., M. A. P.]; Greenbaum Cancer Center and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201 [E. G. Z., M. J. E.]

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.

Footnotes

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↵1 Research support for this work was provided by a VA merit review grant and by NIH Grants CA31770, NS34608, and NS33618.
↵2 To whom requests for reprints should be addressed, at 3181 SW Sam Jackson Park Road, Portland, OR 97201. Phone: (503) 494-5626; Fax: (503) 494-5627; E-mail neuwelte@ohsu.edu.
↵3 The abbreviations used are: BBB, blood-brain barrier; ABR, auditory brainstem response; AUC, area under the curve; CSF, cerebrospinal fluid; STS, sodium thiosulfate.
- Accepted October 13, 1999.
- Received August 13, 1999.
- Revision received October 13, 1999.