Transplatin: A Novel Agent to Mitigate Cisplatin Toxicity

描述（申请人提供）：顺铂广泛用于治疗癌症患者的多种实体肿瘤。然而，该药产生剂量限制的副作用，如耳毒性和肾毒性。虽然在顺铂给药前给患者补水可以降低肾毒性的发生率，但耳毒性仍然是一个重要的问题。顺铂耳毒性在接受神经母细胞瘤等癌症治疗的儿科人群中尤为严重。这一发育阶段的听力丧失会阻碍语言、认知和社会发展。因此，迫切需要开发有效的治疗方法来改善耳毒性。我们假设顺铂耳毒性是通过其增加耳蜗细胞活性氧（ROS）生成的能力介导的。ROS介导外毛细胞（OHCs）、血管纹（SV）和螺旋神经节细胞（SGCs）的损伤。我们和其他人已经证明NADPH氧化酶的NOX3异构体是耳蜗中ROS的主要来源，其被顺铂激活。NOX3产生的ROS在耳蜗基因调控中起关键作用，包括NOX3自身、瞬时受体电位香草样蛋白（TRPV1）通道以及参与炎症和凋亡的基因。在大鼠耳蜗中给予短干扰（si） rna以降低NOX3或TRPV1可减少ohc损伤并减轻顺铂引起的听力损失。信号换能器和转录激活因子1 （STAT1）在将ROS与耳蜗炎症和细胞凋亡耦联中起主要作用。因此，抑制STAT1可防止顺铂耳毒性。有趣的是，作为顺铂的非活性异构体，移植能够通过抑制TRPV1和减少ROS的产生来减轻顺铂的耳毒性。耳保护移植与耳蜗炎症减轻有关。重要的是，与其他耳保护剂不同，移植不会改变顺铂诱导的癌细胞杀伤。这些研究结果为进一步开展顺铂肾毒性缓解移植的临床研究奠定了基础。概述的研究将为移植抗顺铂耳毒性的体内应用提供基础。预计这些信息将用于向美国食品和药物管理局提交新药研究（IND）申请。提出了六个具体目标。目的1和2将分别确定静脉（IV）和口服移植对顺铂耳毒性和肾毒性的疗效。目的3将确定静脉和口服给药后移植的药代动力学。Aim 4将通过基因微阵列研究确定移植保护的分子基础，重点研究顺铂在耳蜗中激活的应激反应和促炎基因途径。目的5将在小鼠肿瘤模型中评估移植对顺铂抗肿瘤疗效的潜在干扰。目标6将使用良好实验室规范（GLP）和非GLP研究确定移植在啮齿动物中的潜在毒性。综上所述，我们相信本研究将为利用移植缓解癌症患者的顺铂毒性提供依据。

DESCRIPTION (provided by applicant): Cisplatin is widely used for treating of a variety of solid tumors in cancer patients. However, this drug produces dose-limiting side effects such as ototoxicity and nephrotoxicity. While the incidence of nephrotoxicity is reduced by hydrating the patients prior to cisplatin administration, ototoxicity remains a significant problem. Cisplatin ototoxicity is particularly serious in the pediatric population undergoing treatment for cancers such as neuroblastoma. Loss of hearing at this developmental stage hampers speech, cognition and social development. Thus, there is an urgent need to develop effective treatments to ameliorate ototoxicity. We have pursued hypothesis that cisplatin ototoxicity is mediated by its ability to increase reactive oxygen species (ROS) generation in cochlear cells. ROS mediate damage to the outer hair cells (OHCs), stria vascularis (SV) and spiral ganglion cells (SGCs). We and others have shown that the NOX3 isoform of NADPH oxidase is the primary source of ROS in the cochlea which is activated by cisplatin. ROS generated by NOX3 play a critical role in the regulation of cochlear genes, including NOX3 itself, transient receptor potential vanilloid (TRPV1) channel and genes involved in the inflammation and apoptosis. Knockdown of NOX3 or TRPV1 by administering short interfering (si) RNAs into the cochlea reduced damage to OHCs and attenuated cisplatin-induced hearing loss in rat. Signal transducer and activator of transcription 1 (STAT1) plays a primary role in coupling ROS to inflammation and apoptosis in the cochlea. As such, inhibition of STAT1 protected against cisplatin ototoxicity. Interestingly, transplatin, an inactive isomer of cisplatin, was able to mitigate cisplatin ototoxicity, by inhibiing TRPV1 and reducing ROS generation. Transplatin otoprotection was associated with reduced cochlear inflammation. Importantly, unlike other otoprotective agents, transplatin did not alter cisplatin-induced killing of cancer cells. These findings provide the basis for pursuing the clinicl development of transplatin for the alleviation of cisplatin oto- and nephrotoxicity. Studies outlined will provide the basis for in vivo application of transplatin against cisplatin ototoxicit. It is anticipated that such information would be used for an Investigational New Drug (IND) filing to the US Food and Drug Administration. Six specific aims are proposed. Aims 1 and 2 will determine the efficacy of intravenous (IV) and oral transplatin against cisplatin ototoxicity and nephrotoxicity, respectively. Aim 3 will determine the pharmacokinetics of transplatin following IV and oral administration. Aim 4 will determine the molecular basis of transplatin protection by gene microarray studies, focusing on stress-responsive and pro- inflammatory gene pathways activated by cisplatin in the cochlea. Aim 5 will assess potential interference by transplatin of cisplatin antitumor efficacy in a mouse tumor model. Aim 6 will determine potential toxicity of transplatin in rodents using good laboratory practice (GLP) and non-GLP studies. Overall, we believe that this study will provide the basis for the use of transplatin to alleviate cisplatin toxicities in cancer patients.