Amelioration of cisplatin ototoxicity by transplatin

描述（申请人提供）：顺铂是一种广泛使用的化疗药物，但会产生剂量限制性副作用，例如肾毒性和耳毒性。我们实验室的最新数据表明，顺铂（顺铂的非活性异构体）可减少培养物中顺铂诱导的耳蜗毛细胞死亡。这种效应可能是通过独特的耳蜗 NADPH 氧化酶亚型 N0X3（耳蜗中 ROS 生成的主要来源）抑制顺铂依赖性活性氧 (ROS) 的产生来介导的。转铂还减少顺铂诱导的细胞内 Ca2 释放，诱导应激蛋白，如瞬时受体电位香草酸受体 1 (TRPV1) 和肾损伤分子 1 (KIM-1)。重要的是，转铂不会抑制顺铂对前列腺癌细胞的杀伤作用。这些发现表明，转铂可能是限制顺铂耳毒性的有用药物。我们将测试转铂可有效对抗顺铂对大鼠的耳毒性的总体假设。这些研究将包括三个具体目标。具体目标 1 将通过全身给药或直接圆窗应用转铂来确定转铂对顺铂引起的听力损失的有效性。将通过听觉脑干反应（ABR）以及使用扫描电子显微镜（SEM）评估耳蜗内毛细胞和外毛细胞的形态来评估耳保护作用。此外，还将评估 NADPH 氧化酶亚基（如 N0X3、Rac1、p22phox 和 p67phox）、应激蛋白（如 TRPV1、KIM-1、热休克蛋白和热休克因子）和凋亡蛋白的表达。具体目标 2 将确定与最佳耳保护相关的最佳转铂给药剂量和时间，并确定顺铂给药后转铂是否有效。具体目标 3 将确定转铂是否会干扰顺铂对严重联合免疫缺陷 (SCID) 小鼠中乳腺癌和前列腺癌肿瘤的生长抑制作用。这些研究将提供重要数据，并为转铂作为药物引起的耳毒性的新型疗法的临床应用奠定基础。转铂的毒性相对较低，可以加快癌症患者从实验室到临床使用该药物的时间。 公共卫生相关性：顺铂相关的听力损失是接受该药物治疗的癌症患者的一个主要问题，特别是儿童。如果我们能够找到一种新方法来预防听力损失而不影响化疗的效果，那将是一个重大突破。这种治疗可以改善癌症患者的生活质量，否则他们将因顺铂治疗引起的听力损失而面临多年的沟通不畅的问题。

DESCRIPTION (provided by applicant): Cisplatin is a widely used chemotherapeutic agent, but which produces dose-limiting side effects, such as nephrotoxicity and ototoxicity. Recent data from our laboratory indicate that the transplatin, an inactive isomer of cisplatin, reduces cisplatin induced death of cochlear hair cell in culture. This effect is presumably mediated by inhibition of cisplatin-dependent generation of reactive oxygen species (ROS) through the unique cochlear NADPH oxidase isoform, N0X3, the major source of ROS generation in the cochlea. Transplatin also decreased cisplatin-induced intracellular Ca2+ release, induction of stress proteins such as transient receptor potential vanilloid receptor 1 (TRPV1) and kidney injury molecule 1 (KIM-1). Importantly, transplatin did not inhibit the killing of prostate cancer cells by cisplatin. These findings suggest that transplatin could be useful a useful drug to limit cisplatin ototoxicity. We would test the overall hypothesis that transplatin is effective against cisplatin ototoxicity in rats. These studies will include three specific aims. Specific Aim 1 will determine the effectiveness of transplatin against cisplatin-induced hearing loss, using either systemic administration or by direct round window application of transplatin. Otoprotection will be assessed by auditory brain stem responses (ABRs) and by assessing the morphology of cochlear inner and outer hair cells, using scanning electron microscopy (SEM). In addition expression of NADPH oxidase subunlts (such as N0X3, Rac1, p22phox and p67phox), stress proteins (such as TRPV1, KIM-1, heat shock proteins and heat shock factor) and apoptotic proteins will also be assessed. Specific Aim 2 will determine the optimal dose and time of transplatin administration linked to optimal ototprotection and to determine whether transplatin is effective following cisplatin administration. Specific Aim 3 will determine whether transplatin interferes with the growth inhibitory action of cisplatin against breast and prostate cancer tumors in severe combined immunodeficient (SCID) mice. These studies will provide significant data and form the basis of the clinical application of transplatin as a novel therapy for drug-induced ototoxicity. The relatively low toxicity of transplatin could hasten the timeline from bench to bedside use of this drug in cancer patients. PUBLIC HEALTH RELEVANCE: Cisplatin-related hearing loss is a major problem among cancer patients treated with this drug, particularly in children. If we are able to find a novel method to prevent the hearing loss without compromising the effectiveness of the chemotherapy, it would be a major breakthrough. Such a treatment could improve the quality of life of cancer patients who would otherwise face many years of poor communication because of hearing loss caused by cisplatin treatment.