Eryılmaz Aylin, Demirci Buket, Günel Ceren, Eliyatkın Nuket, Aktaş Safiye, Kurt Ömürlü İmran, Başal Yeşim, Sağıroğlu Mehmet, Ermişler Barış, Başak Sema
Department of Otorhinolaryngology, Adnan Menderes University School of Medicine, Aydın, Turkey.
J Int Adv Otol. 2015 Dec;11(3):207-11. doi: 10.5152/iao.2015.912.
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.
曲妥珠单抗和拉帕替尼是广泛使用的化疗药物。本研究的目的是评估这些化疗药物可能的耳毒性。
48只大鼠分为6组：第1组（对照组，n = 8）腹腔注射生理盐水7天。第2组（n = 8）和第3组（n = 8）分别腹腔注射单剂量10 mg/kg和30 mg/kg的曲妥珠单抗。第4组（n = 8）以100 mg/kg/天的剂量、第5组（n = 8）以300 mg/kg/天的剂量经口灌胃给予拉帕替尼，持续7天。第6组（n = 8）先腹腔注射单剂量10 mg/kg的曲妥珠单抗；随后，第6组经口灌胃给予剂量为100 mg/kg/天的拉帕替尼，持续7天。在给予任何药物之前，获取畸变产物耳声发射（DPOAE）。在第7天对大鼠再次进行DPOAE测试，之后采集乳突小房。通过末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记（TUNEL）法评估凋亡程度。
根据螺旋神经节TUNEL检测，拉帕替尼300 mg/kg组和拉帕替尼+曲妥珠单抗组（分别为p = 0.008和p = 0.001）与对照组有显著差异。在拉帕替尼100 mg/kg组、拉帕替尼300 mg/kg组和拉帕替尼+曲妥珠单抗组中，柯蒂氏器的凋亡与对照组相比有统计学差异（分别为p = 0.035、p = 0.001和p < 0.001）。曲妥珠单抗仅诱导柯蒂氏器损伤；然而，拉帕替尼诱导柯蒂氏器和螺旋神经节均损伤。当曲妥珠单抗和拉帕替尼联合使用时，柯蒂氏器的损伤程度较高。支持该数据的是，在联合用药期间观察到DPOAE幅值降低。
给予曲妥珠单抗和拉帕替尼会产生耳毒性作用。
