Petremann Mathieu, Tran Van Ba Christophe, Broussy Audrey, Romanet Charlotte, Dyhrfjeld-Johnsen Jonas
SENSORION SA, Montpellier, France.
Otol Neurotol. 2017 Oct;38(9):1355-1361. doi: 10.1097/MAO.0000000000001546.
SENS-401, an oral clinical-stage drug, may reduce cisplatin-induced hearing loss and cochlear damage in an in vivo model.
Cisplatin is commonly associated with hearing loss, causing significant learning and behavioral difficulties in the pediatric cancer population, and for which there are currently no clinical solutions. SENS-401 has previously been shown to improve acoustic trauma-induced hearing loss in vivo.
The effect of SENS-401 (R-azasetron besylate) on cisplatin IC50 values was evaluated in a panel of cisplatin-sensitive cell lines (NIH:OVCAR-3, SK-N-AS, NCI-H460, FaDu). Auditory brainstem response and distortion product otoacoustic emission tests were performed in a rat model of cisplatin-induced hearing-loss (8 mg/kg, day 1) at baseline, and after 14 days of SENS-401 (6.6, 13.2, 26.4 mg/kg/d). Cochlear outer hair cells were counted after immunolabeling for myosin-VIIa.
Cisplatin cytotoxicity was not impacted by the addition of SENS-401 (up to 10 μM) in any of the cell types evaluated. In vivo, all SENS-401 doses significantly improved auditory brainstem response threshold shift (up to 30 dB) and distortion product otoacoustic emission amplitude loss (up to 19 dB) over placebo. Body weight and survival were not significantly different between rats receiving placebo and those receiving 26.4 mg/kg SENS-401. Significantly more surviving outer hair cells were present after SENS-401 treatment compared with placebo (p < 0.001), with up to 11-fold more in the basal turn of the cochlea.
In vivo and in vitro data support the otoprotective potential and tolerability of SENS-401 without impacting chemotherapeutic potential. Oral SENS-401 is a promising candidate for treating cisplatin-induced ototoxicity.
口服临床阶段药物SENS-401可能会减轻顺铂在体内模型中诱导的听力损失和耳蜗损伤。
顺铂通常与听力损失有关，在儿科癌症患者中会导致严重的学习和行为困难，目前尚无临床解决方案。此前已证明SENS-401可改善体内声创伤诱导的听力损失。
在一组顺铂敏感细胞系（NIH:OVCAR-3、SK-N-AS、NCI-H460、FaDu）中评估SENS-401（甲磺酸雷扎塞特）对顺铂IC50值的影响。在顺铂诱导的听力损失大鼠模型（第1天8mg/kg）中，于基线时以及SENS-401（6.6、13.2、26.4mg/kg/天）给药14天后，进行听觉脑干反应和畸变产物耳声发射测试。对肌球蛋白VIIa进行免疫标记后，计数耳蜗外毛细胞。
在所评估的任何细胞类型中，添加SENS-401（高达10μM）均未影响顺铂的细胞毒性。在体内，与安慰剂相比，所有SENS-401剂量均显著改善了听觉脑干反应阈值偏移（高达30dB）和畸变产物耳声发射幅度损失（高达19dB）。接受安慰剂的大鼠与接受26.4mg/kg SENS-401的大鼠之间，体重和存活率无显著差异。与安慰剂相比，SENS-401治疗后存活的外毛细胞明显更多（p<0.001），在耳蜗基部多达11倍。
体内和体外数据支持SENS-401的耳保护潜力和耐受性，且不影响其化疗潜力。口服SENS-401是治疗顺铂诱导的耳毒性的有前景的候选药物。
