National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA.
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA.
Hear Res. 2019 Apr;375:66-74. doi: 10.1016/j.heares.2019.02.006. Epub 2019 Feb 22.
Cisplatin-induced ototoxicity results in significant, permanent hearing loss in pediatric and adult cancer survivors. Elucidating the mechanisms underlying cisplatin-induced hearing loss as well as the development of therapies to reduce and/or reverse cisplatin ototoxicity have been impeded by suboptimal animal models. Clinically, cisplatin is most commonly administered in multi-dose, multi-cycle protocols. However, many animal studies are conducted using single injections of high-dose cisplatin, which is not reflective of clinical cisplatin administration protocols. Significant limitations of both high-dose, single-injection protocols and previous multi-dose protocols in rodent models include high mortality rates and relatively small changes in hearing sensitivity. These limitations restrict assessment of both long-term changes in hearing sensitivity and effects of potential protective therapies. Here, we present a detailed method for an optimized mouse model of cisplatin ototoxicity that utilizes a multi-cycle administration protocol that better approximates the type and degree of hearing loss observed clinically. This protocol results in significant hearing loss with very low mortality. This mouse model of cisplatin ototoxicity provides a platform for examining mechanisms of cisplatin-induced hearing loss as well as developing therapies to protect the hearing of cancer patients receiving cisplatin therapy.
顺铂诱导的耳毒性导致儿科和成年癌症幸存者出现显著且永久性听力损失。阐明顺铂诱导听力损失的机制以及开发减少和/或逆转顺铂耳毒性的疗法一直受到不理想的动物模型的阻碍。临床上，顺铂最常以多剂量、多周期方案给药。然而，许多动物研究使用高剂量顺铂单次注射进行，这与临床顺铂给药方案不符。高剂量单次注射方案和以前的多剂量方案在啮齿动物模型中的显著局限性包括高死亡率和听力敏感性相对较小的变化。这些限制限制了对听力敏感性的长期变化和潜在保护疗法效果的评估。在这里，我们提出了一种优化的顺铂耳毒性小鼠模型的详细方法，该模型使用多周期给药方案，更接近临床观察到的听力损失的类型和程度。该方案导致听力显著丧失，死亡率非常低。这种顺铂耳毒性的小鼠模型为研究顺铂诱导听力损失的机制以及开发保护接受顺铂治疗的癌症患者听力的疗法提供了一个平台。
