Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects.

Abstract

Trastuzumab and lapatinib are widely used chemotherapeutic agents. Our aim in this study was to assess the possible ototoxicity of these chemotherapeutic agents. 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. 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. Administering trastuzumab and lapatinib causes ototoxic effects.