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An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect

Bielefeld, Eric C.a; Tanaka, Chiemib; Chen, Guang-dic; Coling, Donaldc; Li, Mannac; Henderson, Donaldc; Fetoni, Anna R.d

doi: 10.1097/CAD.0b013e32835739fd
Preclinical Reports

Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin’s antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin’s slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin’s ototoxicity, without compromising its antitumor capability.

aDepartment of Speech and Hearing Science, The Ohio State University, Columbus, Ohio

bOregon Hearing Research Center, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon

cCenter for Hearing and Deafness, Department of Communicative Disorders and Sciences, State University of New York at Buffalo, Buffalo, New York, USA

dInstitute of Otolaryngology, Catholic University School of Medicine, Rome, Italy

Correspondence to Eric C. Bielefeld, PhD, Department of Speech and Hearing Science, The Ohio State University, 110 Pressey Hall, 1070 Carmack Road, Columbus, OH 43220, USA Tel: +1 614 292 9436; fax: +1 614 292 7504; e-mail: bielefeld.6@osu.edu

Received February 8, 2012

Accepted June 21, 2012

© 2013 Lippincott Williams & Wilkins, Inc.