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，但它会产生剂量限制的副作用，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TRAPLATIN可以减少顺铂诱导的培养中耳蜗毛细胞的死亡。这种作用可能是通过抑制依赖顺铂产生的活性氧(ROS)，通过独特的耳蜗NADPH氧化酶亚型N0X3来实现的，N0X3是耳蜗中产生ROS的主要来源。转铂还可减少顺铂诱导的细胞内钙释放，减少应激蛋白的诱导，如瞬时受体电位香草样受体1(TRPV1)和肾脏损伤分子1(Kim-1)。重要的是，反铂并没有抑制顺铂对前列腺癌细胞的杀伤作用。这些发现表明，转铂可能是一种有用的药物，可以限制顺铂的耳毒性。我们将检验总体假设，即转铂对大鼠顺铂耳毒性有效。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给药来确定顺铂治疗顺铂引起的听力损失的有效性。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、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将确定与最佳耳廓保护相联系的最佳剂量和时间，并确定顺铂治疗后是否有效。具体目标3将确定在严重联合免疫缺陷(SCID)小鼠中，反铂是否干扰顺铂对乳腺癌和前列腺癌肿瘤的生长抑制作用。这些研究将为反铂作为一种治疗药物所致耳毒性的新疗法的临床应用提供重要的数据和基础。转铂的毒性相对较低，可能会加快癌症患者从长凳到床边使用该药物的时间。 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主要问题，特别是在儿童中。如果我们能够找到一种在不影响化疗效果的情况下预防听力损失的新方法，这将是一个重大突破。这样的治疗可以改善癌症患者的生活质量，否则他们将面临多年的沟通不畅，因为顺铂治疗导致听力损失。

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.