ENDOGENOUS MODULATION OF COCHLEAR INJURY

顺铂在实体瘤最佳治疗中的最佳应用 由于剂量限制，肾脏毒性和耳毒性得以预防。更高 剂量的顺铂可与化学保护剂一起使用，如 二乙基二硫代氨基甲酸酯(DDTC)，可防止顺铂对 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。拟议的研究 试图解决这样一个基本问题：“顺铂的耳毒性 通过操纵耳蜗还原型谷胱甘肽(GSH)含量而改变？ 由此推论，耳蜗还原型谷胱甘肽含量与酶的活性有关 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 受顺铂影响。具体目标是：1)调查 顺铂耳毒性与细胞毒性的关系假说 耳蜗中的抗氧化系统，这种变化是特定的 这个目标组织。听觉脑干测定的生理变化 诱发反应(ABER)测试和耳蜗内电位(EP) 测量将与a)超微结构改变相关，使用 Corti细胞器的扫描电子显微镜观察及透射 血管纹的电子显微镜；和b)生化 耳蜗肌组织中抗氧化系统的变化 非靶组织，肝脏和心脏，2)检验假设 顺铂引起的部分或全部耳毒性损伤是通过 耳毒性代谢物，如GSH加合物，3)检验假设 DDTC预防顺铂耳毒性的机制是通过 防腐剂对耳蜗内抗氧化系统的影响，4)研究 顺铂在耳毒性大鼠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。这个 这项调查使用的技术将涉及三个人的专业知识 调查人员即生理测量(ABER和EP)， 形态研究(扫描电子显微镜和透射电子显微镜)生化和代谢研究： 具有紫外和电化学检测(GSH和GSSG)的高效液相色谱， 抗氧化酶和谷胱甘肽途径的其他酶使用 原子吸收分光光度法与药代动力学研究 铂含量的分光光度测定法。这些研究应该提供新的 顺铂耳毒性机制的研究进展 预防因使用本产品而产生的剂量限制副作用 救命的化疗药剂。

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.