Transplatin: A Novel Agent to Mitigate Cisplatin Toxicity

转铂：一种减轻顺铂毒性的新型药物

基本信息

批准号：
9288153
负责人：
Vickram Ramkumar
金额：
$ 30.19万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288153
关键词：
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 Hydration status 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 Rattus Reactive Oxygen Species Regimen Regulation Rodent Role SCID Mice STAT1 protein Sensorineural Hearing Loss Small Interfering RNA Social Development Solid Neoplasm Source Speech Steroids Stress Stria Vascularis TRP channel Testing Toxic effect United States Food and Drug Administration Vanilloid Xenograft procedure analog antigen challenge antioxidant therapy cancer cell cancer therapy chemotherapy cytokine effective therapy experience ganglion cell good laboratory practice hearing impairment in vivo killings knock-down mouse model nephrotoxicity novel ototoxicity public health relevance receptor spiral ganglion transplatin treatment group tumor uptake

项目摘要

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多种实体瘤。然而，这种药物会产生剂量限制性副作用，例如耳毒性和肾毒性。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大问题。顺铂的耳毒性对于接受神经母细胞瘤等癌症治疗的儿科人群尤其严重。在这个发育阶段丧失听力会阻碍言语、认知和社会发展。因此，迫切需要开发有效的治疗方法来改善耳毒性。我们假设顺铂的耳毒性是由其增加耳蜗细胞中活性氧 (ROS) 生成的能力介导的。 ROS 介导对外毛细胞 (OHC)、血管纹 (SV) 和螺旋神经节细胞 (SGC) 的损伤。我们和其他人已经证明，NADPH 氧化酶的 NOX3 亚型是顺铂激活的耳蜗中 ROS 的主要来源。 NOX3产生的ROS在耳蜗基因的调节中发挥着关键作用，包括NOX3本身、瞬时受体电位香草酸（TRPV1）通道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 NOX3 或 TRPV1，可减少对 OHC 的损伤，并减轻顺铂引起的大鼠听力损失。信号转导器和转录激活剂 1 (STAT1) 在 ROS 与耳蜗炎症和细胞凋亡的耦合中发挥主要作用。因此，抑制 STAT1 可防止顺铂耳毒性。有趣的是，顺铂（顺铂的非活性异构体）能够通过抑制 TRPV1 和减少 ROS 生成来减轻顺铂的耳毒性。转铂耳保护与减少耳蜗炎症有关。重要的是，与其他耳保护剂不同，转铂不会改变顺铂诱导的癌细胞杀伤作用。这些发现为寻求转铂缓解顺铂耳毒性和肾毒性的临床开发奠定了基础。概述的研究将为体内应用转铂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和药物管理局提交研究性新药 (IND) 申请。提出了六项具体目标。目标 1 和 2 将确定静脉注射 (IV) 和口服铂分别对抗顺铂耳毒性和肾毒性的功效。目标 3 将确定静脉注射和口服给药后转铂的药代动力学。目标 4 将通过基因微阵列研究确定转铂保护的分子基础，重点关注顺铂在耳蜗中激活的应激反应和促炎基因途径。目标 5 将评估转铂对小鼠肿瘤模型中顺铂抗肿瘤功效的潜在干扰。目标 6 将利用良好实验室规范 (GLP) 和非 GLP 研究确定转铂对啮齿类动物的潜在毒性。总的来说，我们相信这项研究将为使用转铂减轻癌症患者的顺铂毒性提供基础。