ENDOGENOUS MODULATION OF OTOTOXICITY OF CISPLATIN

顺铂耳毒性的内源性调节

• 批准号: 2127726
• 负责人: LEONARD P RYBAK
• 金额: $ 17.64万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2127726
• 关键词: antioxidants; atomic absorption spectrometry; audiometry; auditory nuclei; catalase; chemoprevention; cis platinum compound; cochlea; cochlear microphonic potentials; drug interactions; ear pharmacology; electron microscopy; enzyme activity; glutathione; glutathione peroxidase; glutathione reductase; glutathione transferase; laboratory rat; lipid peroxides; malonaldehyde; organ of Corti; ototoxin; pharmacokinetics; superoxide dismutase; thiocarbamate

The optimal use of cisplatin for the best treatment of solid tumors has been prevented because of dose limiting nephro-and ototoxicity. Higher doses of cisplatin may be used with chemoprotectants such as diethyldithiocarbamate (DDTC), which prevents cisplatin toxicity for the kidney and bone marrow. Our preliminary data suggest that DDTC can also prevent cisplatin ototoxicity in an animal model. The proposed research seeks to address the basic question, "Can the ototoxicity of cisplatin be altered by manipulating the glutathione (GSH) content of the cochlea?" A corollary is that the GSH content of the cochlea is related to enzymes of the antioxidant system [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] and the enzymes glutathione reductase (GR) and glutathione-S-transferase (GST) and that these enzymes are affected by cisplatin. The specific aims are: 1) to investigate the hypothesis that cisplatin ototoxicity is related to the diminution of the antioxidant system in the cochlea, and that such changes are specific for this target tissue. Physiological changes measured with auditory brainstem evoked response (ABER) testing and endocochlear potential (EP) measurements will be correlated with a) ultrastructural alterations using scanning electron microscopy (SEM) of the organ of Corti and transmission electron microscopy (TEM) of the stria vascularis; and b) biochemical changes in the antioxidant system of the cochlea in comparison to nontarget tissues, the liver and heart, 2) to test the hypothesis that some or all of the ototoxic injury caused by cisplatin is mediated by ototoxic metabolites such as GSH adducts, 3) to examine the hypothesis that the prevention of cisplatin ototoxicity by DDTC is mediated by preservatives of the antioxidant system in the cochlea, 4) to study the pharmacokinetics of cisplatin in plasma and cochlear tissues in ototoxic rats and in animals receiving cisplatin plus the rescue agent, DDTC. The techniques used for this investigation will involve the expertise of three investigators namely physiological measurements (ABER and EP), morphological studies (SEM and TEM) biochemical and metabolic studies: (HPLC) with ultraviolet and electrochemical detection (GSH and GSSG), antioxidant enzymes and other enzymes of the glutathione pathway using spectrophotometry and pharmacokinetic studies by atomic absorption spectrophotometry of platinum levels. These studies should provide new insights into the mechanisms of cisplatin ototoxicity and mechanisms for protection from this dose-limiting side effect arising from use of this life-saving chemotherapeutic agent.

顺铂的最佳使用是实体瘤的最佳治疗， 由于剂量限制性肾毒性和耳毒性，更高 顺铂的剂量可以与化学保护剂一起使用 二乙基二硫代氨基甲酸酯（DDTC），它可以防止顺铂的毒性， 肾脏和骨髓我们的初步数据表明，DDTC也可以 在动物模型中预防顺铂耳毒性。拟议研究 寻求解决基本问题，“顺铂的耳毒性是否可以 通过操纵耳蜗的谷胱甘肽（GSH）含量来改变？“一个 由此推论，耳蜗的GSH含量与 抗氧化系统[超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和 谷胱甘肽过氧化物酶（GSH-Px）]和谷胱甘肽还原酶 (GR)和谷胱甘肽-S-转移酶（GST），这些酶是 受到顺铂的影响具体目的是：1）调查 假设顺铂耳毒性与 耳蜗中的抗氧化系统，这种变化是特定的， 这个目标组织。听觉脑干的生理变化 诱发反应（ABER）测试和耳蜗内电位（EP） 测量结果将与a）使用 Corti器的扫描电子显微镜（SEM）和透射电镜（TEM） 血管纹的电子显微镜检查（TEM）;和B）生物化学 耳蜗抗氧化系统的变化， 非靶组织，肝脏和心脏，2）为了检验假设， 顺铂引起的部分或全部耳毒性损伤是由 耳毒性代谢物，如GSH加合物，3）检查假设 DDTC对顺铂耳毒性的预防作用是由 耳蜗抗氧化系统的防腐剂，4）研究 顺铂在耳中毒患者血浆和耳蜗组织中的药代动力学 大鼠和接受顺铂加救援剂DDTC的动物。的 用于这项调查的技术将涉及三个专业知识 研究人员即生理测量（ABER和EP）， 形态学研究（SEM和TEM）生化和代谢研究： （HPLC）与紫外和电化学检测（GSH和GSSG）， 抗氧化酶和谷胱甘肽途径的其他酶， 原子吸收分光光度法和药代动力学研究 铂水平的分光光度法。这些研究将提供新的 顺铂耳毒性的机制和机制的见解 保护免受这种剂量限制性副作用所产生的使用这种 挽救生命的化疗剂