Amelioration of cisplatin ototoxicity by transplatin

描述（由申请人提供）：顺铂是一种广泛使用的化疗剂，但其产生剂量限制性副作用，如肾毒性和耳毒性。我们实验室的最新数据表明，顺铂的非活性异构体transplatin可减少顺铂诱导的耳蜗毛细胞死亡。这种效应可能是通过抑制顺铂依赖性活性氧（ROS）的产生介导的，活性氧的产生是通过独特的耳蜗NADPH氧化酶同种型NOX 3（耳蜗中ROS产生的主要来源）进行的。Transplatin还减少顺铂诱导的细胞内Ca 2+释放，诱导应激蛋白，如瞬时受体电位香草酸受体1（TRPV 1）和肾损伤分子1（KIM-1）。重要的是，transplatin不抑制顺铂对前列腺癌细胞的杀伤。这些发现表明，transplatin可能是一个有用的药物，以限制顺铂耳毒性。我们将检验transplatin对大鼠顺铂耳毒性有效的总体假设。这些研究将包括三个具体目标。具体目标1将确定transplatin对顺铂诱导的听力损失的有效性，使用transplatin的全身给药或直接圆窗应用。将通过听觉脑干反应（ABR）和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。此外，还将评估NADPH氧化酶亚基（如N 0X 3、Rac 1、p22 phox和p67 phox）、应激蛋白（如TRPV 1、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transplatin给药的最佳剂量和时间，并确定transplatin在顺铂给药后是否有效。具体目标3将确定在严重联合免疫缺陷（SCID）小鼠中transplatin是否干扰顺铂对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的数据，并形成的基础上，transplatin作为一种新的治疗药物引起的耳毒性的临床应用。相对较低的毒性transplatin可以加快时间轴从实验室到床边使用这种药物在癌症患者。 公共卫生相关性：顺铂相关性听力损失是接受该药物治疗的癌症患者的主要问题，特别是儿童。如果我们能够找到一种新的方法来预防听力损失，而不影响化疗的有效性，这将是一个重大突破。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。

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.