J Int Adv Otol 2015; 11(3): 207-11 • DOI: 10.5152/iao.2015.912 Original Article INTRODUCTION Trastuzumab (Herceptin®; Genentech, California, San Francisco, USA) is used for treating human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Trastuzumab is a humanized recombinant monoclonal antibody that acts on the extracellular por- tion of the HER2 protein [1] . Lapatinib (Tykerb®; Glaxo-Smith Kline) is a tyrosine kinase inhibitor that suppresses epidermal growth factor 1 (EGF-1) and intracellular phosphorylation of the HER-2/neu receptor. In studies with trastuzumab, cardiotoxicity is stated as the most common side effect [2] . The known side effects of lapatinib are the reduction of the left ventricular ejection fraction, inter- stitial lung disease/pneumonitis, dizziness, fatigue, severe diarrhea, dry cough, white sores in the mouth or lips, nosebleeds, nausea, stomach pain, jaundice, loss of appetite, aspartate aminotransferase (AST) changes, alanine aminotransferase (ALT) changes, and hematological changes [3, 4] . To our knowledge, the ototoxicity of these chemotherapeutic agents has not yet been studied. The aim of this study is to identify whether these agents are ototoxic in rats and to determine the dose dependency of the ototoxicity. MATERIALS and METHODS The study was approved by the Animal Experiments Ethical Committee of Adnan Menderes University (64583101/2013/038). A total of 48 male rats aged 4–8 months were randomly divided into six groups. All rats were subjected to distortion product oto- acoustic emissions (DPOAE) on the first day after being anesthetized with ketamine/xylazine. Group 1 (control group) received This article has won the first poster prize (TKBBV Prof. Dr. Orhan SUNAR poster award) in the 36 th Turkish National Congress of Otorhinolaryngology and Head and Neck Surgery 5-9 November 2014, Antalya, Turkey. Corresponding Address: Aylin Eryılmaz, E-mail: draylineryilmaz@gmail.com Submitted: 28.01.2015 Revision received: 04.03.2015 Accepted: 15.07.2015 Copyright 2015 © The Mediterranean Society of Otology and Audiology 207 Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects OBJECTIVE: Trastuzumab and lapatinib are widely used chemotherapeutic agents. Our aim in this study was to assess the possible ototoxicity of these chemotherapeutic agents. MATERIALS and METHODS: Forty-eight rats were divided into six groups: Group 1 (control, n=8) received intraperitoneal saline for 7 days. Group 2 (n=8) and Group 3 (n=8) received 10 mg/kg and 30 mg/kg single doses of intraperitoneal trastuzumab, respectively. Lapatinib was administered by oral gavage to Group 4 (n=8) at 100 mg/kg/day and to group 5 (n=8) at 300 mg/kg/day for 7 days. Group 6 (n=8) received only one dose of 10 mg/kg intraperitoneal trastuzumab; subsequently, Group 6 received one dose of lapatinib at 100 mg/kg/day by oral gavage for 7 days. Before any medication was administered, distortion product emissions (DPOAE) were obtained. DPOAE tests were performed again on the rats on day 7, after which the mastoid bullas were harvested. The apoptosis degree was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) procedure. RESULTS: The lapatinib 300 and lapatinib+trastuzumab groups (p=0.008 and p=0.001, respectively) were significantly different from the control group according to the spiral ganglion TUNEL. Apoptosis in the organ of corti was statistically different compared with the control group in the lapatinib 100, lapatinib 300, and lapatinib+trastuzumab groups (p=0.035, p=0.001, and p<0.001, respectively). Trastuzumab induced damage in only the organ of corti; however, lapatinib induced damage in both the organ of corti and spiral ganglion. The degree of the damage in the organ of corti was high when trastuzumab and lapatinib were concomitantly used. Supporting this data, a reduction in DPOAE amplitudes was observed during the combined usage of the drugs. CONCLUSION: Administering trastuzumab and lapatinib causes ototoxic effects. KEYWORDS: Lapatinib, ototoxicity, trastuzumab Aylin Eryılmaz, Buket Demirci, Ceren Günel, Nuket Eliyatkın, Safye Aktaş, İmran Kurt Ömürlü, Yeşim Başal, Mehmet Sağıroğlu, Barış Ermişler, Sema Başak Department of Otorhinolaryngology, Adnan Menderes University School of Medicine, Aydın, Turkey (AE, CG, YB, BE, SB) Department of Medical Pharmacology, Adnan Menderes University School of Medicine, Aydın, Turkey (BD) Department of Pathology, Adnan Menderes University School of Medicine, Aydın, Turkey (NE) Department of Basic Oncology, Dokuz Eylül University School of Medicine, İzmir, Turkey (SA) Department of Biostatistics, Adnan Menderes University School of Medicine, Aydın, Turkey (İKÖ) Department of Oncology, Turkish Ministry of Health, Balıkesir, Turkey (MS)