Transplatin: A Novel Agent to Mitigate Cisplatin Toxicity

转铂：一种减轻顺铂毒性的新型药物

• 批准号: 8579608
• 负责人: Vickram Ramkumar
• 金额: $ 29.94万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579608
• 关键词: Accounting; Acute Kidney Failure; Adverse effects; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Attenuated; Bilateral; Breast Cancer Cell; Cancer Patient; Carboplatin; Cell Death; Cells; Childhood; Chronic; Cisplatin; Clinical; Clinical Trials; Cochlea; Cognition; Copper; Couples; Coupling; DNA Alkylation; Data; Development; Dose-Limiting; Drug Kinetics; Generations; Genes; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Intravenous; Investigational Drugs; Isomerism; Laboratories; Labyrinth; Link; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of testis; Mediating; Modeling; Molecular; Mus; NADPH Oxidase; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Oral; Oral Administration; Outer Hair Cells; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Play; Population; Protective Agents; Protein Isoforms; Proteins; RNA; Rattus; Reactive Oxygen Species; Regimen; Regulation; Rodent; Role; SCID Mice; STAT1 protein; Sensorineural Hearing Loss; Social Development; Solid Neoplasm; Source; Speech; Staging; Steroids; Stress; Stria Vascularis; TRP channel; Testing; Toxic effect; United States Food and Drug Administration; Vanilloid; Xenograft procedure; analog; antigen challenge; antioxidant therapy; base; cancer cell; cancer therapy; chemotherapy; cytokine; effective therapy; experience; ganglion cell; good laboratory practice; hearing impairment; immunodeficient mouse model; in vivo; killings; meetings; nephrotoxicity; novel; ototoxicity; public health relevance; receptor; spiral ganglion; transplatin; tumor; uptake

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.

描述（由申请人提供）：顺铂被广泛用于治疗癌症患者的多种实体瘤。但是，该药物会产生限制剂量的副作用，例如耳毒性和肾毒性。虽然在给药之前通过对患者进行补水，但肾毒性的发生率降低了，但耳毒性仍然是一个重要的问题。在接受神经母细胞瘤等癌症治疗的小儿种群中，顺铂耳毒性尤其严重。在此发展阶段失去听力会阻碍言论，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。我们提出了假设，即顺铂耳毒性是由其增加人工耳蜗中活性氧（ROS）产生的能力所介导的。 ROS介导对外毛细胞（OHC），Stria Vascularis（SV）和螺旋神经节细胞（SGC）的损伤。我们和其他人已经表明，NADPH氧化酶的NOX3同工型是通过顺铂激活的耳蜗中ROS的主要来源。 NOX3产生的ROS在调节人工耳蜗基因的调节中起着关键作用，包括NOX3本身，瞬态受体电位香草素（TRPV1）通道以及涉及炎症和凋亡的基因。通过将短短干扰（Si）RNA施加到耳蜗中，敲低NOX3或TRPV1可减少对OHC的损害，并减弱顺铂诱导的大鼠听力损失。转录1（STAT1）的信号传感器和激活因子在将ROS与耳蜗中的炎症和凋亡偶联中起主要作用。因此，抑制STAT1免受顺铂耳毒性的保护。有趣的是，通过抑制TRPV1并减少ROS的产生，可以减轻顺铂的非活性异构体移动异构体。移植蛋白的触发剂与人工耳蜗炎症减少有关。重要的是，与其他耳效剂不同，移植蛋白不会改变顺铂诱导的癌细胞杀死。这些发现为追求移植蛋白的临床发展提供了基础，以减轻顺铂和肾毒性。 概述的研究将为替代蛋白与顺铂耳毒素的体内应用提供基础。预计此类信息将用于向美国食品药品监督管理局提交的调查新药（IND）。提出了六个具体目标。 AIM 1和2将分别确定静脉内（IV）和口服移植素对顺铂耳毒性和肾毒性的疗效。 AIM 3将确定IV和口服给药后移植蛋白的药代动力学。 AIM 4将通过基因微阵列研究来确定移植蛋白保护的分子基础，重点是由顺铂在耳蜗中激活的应激反应性和促炎性基因途径。 AIM 5将评估小鼠肿瘤模型中顺铂抗肿瘤功效的移植蛋白的潜在干扰。 AIM 6将使用良好的实验室实践（GLP）和非GLP研究来确定移植蛋白在啮齿动物中的潜在毒性。总体而言，我们认为这项研究将为使用移植素减轻癌症患者的顺铂毒性提供基础。