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）：顺铂广泛用于治疗癌症患者的各种实体瘤。然而，这种药物产生剂量限制性副作用，如耳毒性和肾毒性。虽然肾毒性的发生率通过在顺铂给药之前使患者水合而降低，但耳毒性仍然是一个重要问题。顺铂耳毒性在接受癌症（如神经母细胞瘤）治疗的儿科人群中特别严重。在这一发育阶段丧失听力会阻碍语言、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。我们一直认为顺铂的耳毒性是通过其增加耳蜗细胞中活性氧（ROS）产生的能力来介导的。ROS介导外毛细胞（OHC）、血管纹（SV）和螺旋神经节细胞（SGCs）的损伤。我们和其他人已经表明，NADPH氧化酶的NOX3同种型是耳蜗中ROS的主要来源，其被顺铂激活。NOX3产生的活性氧在耳蜗基因调控中起重要作用，包括NOX3本身、瞬时受体电位香草酸通道（TRPV1）以及参与炎症和凋亡的基因。通过向耳蜗中施用短干扰（si）RNA来敲低NOX 3或TRPV 1减少了对OHC的损伤并减轻了大鼠中顺铂诱导的听力损失。信号转导子和转录激活子1（STAT1）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可保护顺铂耳毒性。有趣的是，顺铂的非活性异构体transplatin能够通过抑制TRPV 1和减少ROS的产生来减轻顺铂的耳毒性。transsplatin耳保护与耳蜗炎症减少有关。重要的是，与其他耳保护剂不同，transplatin不改变顺铂诱导的癌细胞杀伤。这些发现为临床开发transplatin减轻顺铂的耳肾毒性提供了依据。 这些研究将为体内应用transplatin对抗顺铂耳毒性提供基础。预计此类信息将用于向美国食品药品监督管理局提交研究性新药（IND）申请。提出了六个具体目标。目的1和2将分别确定静脉内（IV）和口服transplatin对顺铂耳毒性和肾毒性的疗效。目的3将确定IV和口服给药后反铂的药代动力学。目的4将通过基因芯片研究确定顺铂保护的分子基础，重点是顺铂在耳蜗中激活的应激反应和促炎基因通路。目的5将在小鼠肿瘤模型中评估transplatin对顺铂抗肿瘤疗效的潜在干扰。目的6将使用药物非临床研究质量管理规范（GLP）和非GLP研究确定顺铂在啮齿动物中的潜在毒性。总之，我们认为这项研究将为使用transplatin减轻癌症患者的顺铂毒性提供依据。