PREVENTION OF HEARING LOSS BY OTOPROTECTIVE AGENTS

顺铂(CDDP)是临床上最常用的耳毒素。 顺铂引起的听力损失可能很严重，而且几乎总是 永久的。因为顺铂被用于更广泛的癌症和 随着剂量的增加，顺铂的耳毒性也在增加。 临床重要性。此外，顺铂引起的耳毒性现在是最大的 顺铂化疗的常见剂量限制因素。 拟议研究的目的是选择最有效的 每类顺铂保护剂对大鼠的保护作用 模特。耳毒性将通过听觉脑干反应进行评估 耳蜗毛细胞阈值、扫描电子显微镜(SEM) 血管纹的透射电子显微镜观察。 体重减轻，作为衡量一般健康的一项指标，也将进行评估。 因为肾毒性是第二个最常见的剂量限制因素 对于顺铂化疗，因为许多保护剂是 对耳毒性和肾毒性都有效，我们还将测量 每种动物的肌酸值。然而，这笔赠款的主要目的是 就是开发耳保护剂和预防听力损失。 所包括的药剂类别有：含硫化合物、防老剂、防老剂 氧化剂/自由基清除剂和类固醇。所选的每个代理 符合以下标准：有文件证明该特工是 对顺铂耳毒性和/或肾毒性的保护作用，NO 加剧顺铂的其他毒性，且不抑制顺铂的抗肿瘤作用 肿瘤疗效或无机制抑制抗肿瘤疗效。全 制剂还必须适合于人类使用。 对照组，每组11只动物，将包括一个处理组(16 mg/kg CDDP)，以及未处理(等量生理盐水)对照组。 对于除CDDP外还接受保护剂的动物，首先 将获得剂量反应曲线(每级5只动物)以确定 每个药剂的最佳剂量水平。然后每个人中的特工 将比较药物的类别(每组最低11只动物 提供最佳保护的剂量水平。 实验时间安排如下：第一年：含硫 化合物第2年：抗氧化剂/自由基清除剂第3年： 类固醇。 在资助的第四年和第五年，每个项目的最佳代理 上述实验将在各种组合中进行测试。“最好的” 将根据耳保护的主要标准选择代理，并且 肾脏保护的次要标准，因为目前耳毒性是 大鼠的原发和肾毒性及次级剂量限制毒性 CDDP。 希望这些实验能让我们发展得更好 接受顺铂化疗的患者的方案，以便他们可以 接受足够大的顺铂剂量来治愈他们的癌症，而不需要副作用 听力损失的影响。

Cisplatin (CDDP) is the most potent ototoxin in common clinical use. CDDP induced hearing loss can be severe and is almost always permanent. As CDDP is used for a wider variety of cancers and with increasingly higher dosing, CDDP induced ototoxicity is of increasing clinical importance. Further, CDDP induced ototoxicity is now the most common dose limiting factor for CDDP chemotherapy. The purpose of the proposed studies is to select the most effective protective agent from each class of CDDP protective agents in a rat model. Ototoxicity will be assessed by auditory brainstem response threshold, scanning electron microscopy of the cochlear hair cells (SEM) and transmission electron microscopy (TEM) of the stria vascularis. Weight loss, as a measure of general health, will also be assessed. Because nephrotoxicity is the second most common dose limiting factor for CDDP chemotherapy, and because many protective agents are effective for both ototoxicity and nephrotoxicity, we will also measure creatinine for each animal. However the primary purpose of this grant is to develop otoprotective agents and to prevent hearing loss. The classes of agents included are: sulfur containing compounds, anti- oxidants/free radical scavengers, and steroids. Each agent selected meets the following criteria: documented evidence that the agent is protective against CDDP ototoxicity and/or nephrotoxicity, no exacerbation of other CDDP toxicities, and no inhibition of CDDP anti- tumor efficacy or no mechanism for inhibition of anti-tumor efficacy. All agents must also be suitable for use in humans. Control groups, of 11 animals each, will include a treated (16 mg/kg CDDP), and an untreated (equivalent volume of saline) control group. For animals receiving protective agents in addition to the CDDP, first dose response curves (5 animals per level) will be obtained to determine the optimal dosing level for each agent. Then the agents within each class of agents will be compared (11 animals per group at the lowest dosing level that provides optimal protection. The schedule of experiments is as follows: Year 1: Sulfur containing compounds Year 2: Anti-oxidants/free radical scavengers Year 3: Steroids. In the fourth and five year of the grant, the best agent of each of the above experiments will be tested in various combinations. The "best" agent will be selected on the primary criterion of otoprotection and the secondary criterion of nephroprotection because currently ototoxicity is the primary and nephrotoxicity the secondary dose limiting toxicity for CDDP. It is hoped that these experiments will allow us to develop better protocols for patients receiving CDDP chemotherapy so that they may receive CDDP dosing high enough to cure their cancer without the side effect of hearing loss.