title: An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect.
abstract: 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.
authors: Department of Speech and Hearing Science, The Ohio State University, Columbus, Ohio 43220, USA. bielefeld.6@osu.edu
authors: Eric C
authors: EC
authors: Bielefeld
authors: Chiemi
authors: C
authors: Tanaka
authors: Guang-di
authors: GD
authors: Chen
authors: Donald
authors: D
authors: Coling
authors: Manna
authors: M
authors: Li
authors: Donald
authors: D
authors: Henderson
authors: Anna R
authors: AR
authors: Fetoni
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D019073:HT29 Cells; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C580957:KX1-004; D047428:Protein Kinase Inhibitors; D019061:src-Family Kinases; D002945:Cisplatin