Transplatin: A Novel Agent to Mitigate Cisplatin Toxicity

描述(申请人提供)：顺铂被广泛用于治疗癌症患者的各种实体肿瘤。然而，这种药物会产生耳毒性和肾毒性等剂量限制的副作用。虽然在顺铂给药前给患者补充水分可以减少肾毒性的发生率，但耳毒性仍然是一个重要的问题。顺铂的耳毒性在接受神经母细胞瘤等癌症治疗的儿童人群中尤其严重。听力损失在这个发育阶段阻碍了言语、认知和社会发展。因此，迫切需要开发有效的治疗方法来减轻耳毒性。我们提出的假设是，顺铂的耳毒性是由其增加耳蜗细胞中的ROS生成所介导的。ROS介导对外毛细胞、血管纹和螺旋神经节细胞的损伤。我们和其他人已经证明，NADPH氧化酶的NOX3亚型是由顺铂激活的耳蜗中ROS的主要来源。NOX3产生的ROS在耳蜗基因调控中起着关键作用，这些基因包括NOX3本身、瞬时受体电位香草素通道(TRPV1)以及参与炎症和细胞凋亡的基因。通过给予短干扰(Si)RNA将NOX3或TRPV1基因敲除到耳蜗内，减少了对内耳毛细胞的损伤，并减轻了顺铂引起的听力损失。信号转导和转录激活子1(STAT1)在ROS与耳蜗炎症和细胞凋亡的偶联中起主要作用。因此，抑制STAT1对顺铂耳毒性有保护作用。有趣的是，顺铂的一种非活性异构体Transplatin能够通过抑制TRPV1和减少ROS的产生来减轻顺铂的耳毒性。转铂的耳保护作用与减轻耳蜗炎有关。重要的是，与其他耳保护剂不同，反铂不会改变顺铂诱导的对癌细胞的杀伤。这些结果为进一步研究顺铂对耳、肾毒性的临床应用奠定了基础。概述的研究将为体内应用转铂对抗顺铂耳毒提供基础。预计这些信息将用于向美国食品和药物管理局(FDA)提交调查用新药(IND)。提出了六个具体目标。AIMS 1和AIMS 2将分别确定静脉(IV)和口服转铂对抗顺铂耳毒性和肾毒性的疗效。目的3测定静脉和口服给药后转铂的药代动力学。目的4将通过基因芯片研究确定转铂保护的分子基础，重点研究顺铂激活的耳蜗应激反应和促炎基因通路。目的5将评估顺铂在小鼠肿瘤模型中对顺铂抗肿瘤效果的潜在干扰。目的6将使用良好实验室规范(GLP)和非GLP研究来确定反铂对啮齿动物的潜在毒性。总体而言，我们相信这项研究将为使用顺铂减轻癌症患者的顺铂毒性提供基础。

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.