NEPHROTOXICITY OF THE CANCER DRUG IFOSFAMIDE

抗癌药物异环磷酰胺的肾毒性

• 批准号: 2666166
• 负责人: MARIANNA J ZAMLAUSKI
• 金额: $ 10.11万
• 依托单位: BALL STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2666166
• 关键词: acetaldehyde; adenosine triphosphate; bioenergetics; drug adverse effect; drug metabolism; glutathione; ifosfamide; isolation perfusion; malonaldehyde; organ culture; oxidative stress; pharmacokinetics; renal toxin

DESCRIPTION: (Adapted from the Investigator's Abstract) The long-term objective of this proposal is to provide insight into possible mechanisms by which the cancer drug ifosfamide causes kidney dysfunction. Ifosfamide is used to treat solid tumors in both adults and children. A nephrotoxic side effect of ifosfamide treament is the development of Fanconi syndrome. This syndrome results in generalized dysfunction of proximal tubule cells and may lead to renal failure. The ifosfamide metabolites chloroacetaldehyde and 4-hydroxyifosfamide have been implicated as possible causes of renal toxicity in patients treated with ifosfamide. The mechanism by which these ifosfamide metabolites induce kidney dysfunction is not understood. The specific aims are: 1) to investigate whether oxidant stress is a possible mechanisms by which chloroacetalydehyde causes Fanconi syndrome in the isolated perfused rat kidney preparation; 2) to investigate whether energy depletion is a possible mechanisms by which chloroacetaldehyde caused Fanconi syndrome in the isolated perfused rat kidney preparation; and 3) to investigate whether 4-hydroxyifosfamide causes Fanconi syndrome in the isolated perfused rat kidney preparation and whether the dysfunction is due to oxidant stress or energy depletion. Oxidant stress will be assessed by determining changes in the ratio of reduced to oxidized glutathione and the malondialdehyde content in the kidney. Energy depletion will be assessed by determining the kidney ATP content. Results from the proposed research will contribute to our understanding of the mechanism by which the cancer drug ifosfamide caused renal injury. Such information could then lead to treatments that may prevent the injury to the kidney.

描述：（根据调查员的摘要改编）长期 该提议的目的是通过洞悉可能的机制 癌症药物IFOSFAMIDE会引起肾功能障碍。 ifosfamide是 用于治疗成人和儿童的实体瘤。 肾毒性方面 ifosfamide障碍的影响是范科尼综合征的发展。 这 综合征导致近端小管细胞的普遍功能障碍，可能 导致肾衰竭。 Ifosfamide代谢物氯乙醛和 4-羟基二酰胺已被视为肾脏的可能原因 用ifosfamide治疗的患者的毒性。 这些机制 ifosfamide代谢物诱导肾功能障碍。 这 具体目的是：1）研究氧化应激是否可能 氯乙醛甲醛引起范科尼综合征的机制 孤立的灌注大鼠肾脏制剂； 2）调查能​​量是否 耗竭是氯乙醛引起的可能机制 孤立的灌注大鼠肾脏制剂中的芬科尼综合征；和3）到 调查4-羟基二酰胺是否引起Fanconi综合征 孤立的灌注大鼠肾脏的准备以及功能障碍是否到期 氧化应激或能量消耗。 氧化应激将通过 确定还原与氧化谷胱甘肽的比率变化和 肾脏中的丙二醛含量。 能量耗竭将通过 确定肾脏ATP含量。 拟议研究的结果将 有助于我们理解癌症药物的机制 Ifosfamide造成肾脏损伤。 这样的信息可能会导致 可能阻止肾脏受伤的治疗。