NEPHROTOXICITY OF THE CANCER DRUG IFOSFAMIDE

描述：(改编自《调查员摘要》)长期 本提案的目标是通过以下方式深入了解可能的机制 抗癌药物异环磷酰胺会导致肾功能障碍。异环磷酰胺是 用于治疗成人和儿童的实体肿瘤。有肾毒性的一面 异环磷酰胺治疗的效果是Fanconi综合征的发展。这 综合征导致近端小管细胞泛发性功能障碍，并可能 导致肾功能衰竭。异环磷酰胺代谢物氯乙醛和 4-羟基异环磷酰胺被认为是导致肾脏疾病的可能原因 异环磷酰胺治疗患者的毒性。它们通过的机制 异环磷酰胺代谢物引起肾功能障碍的机制尚不清楚。这个 具体目标是：1)调查氧化应激是否可能 氯乙醛引起Fanconi综合征的机制 体外灌流大鼠肾脏制备；2)研究能量 消耗是氯乙醛引起的一种可能机制 Fanconi综合征在离体灌流大鼠肾脏制备中的作用；3) 研究4-羟基异环磷酰胺是否导致Fanconi综合征 大鼠离体血灌流肾制备及其是否存在功能障碍 氧化应激或能量耗尽。氧化应激将通过以下方式评估 测定还原型谷胱甘肽与氧化型谷胱甘肽比率的变化 肾组织中丙二醛含量。能源消耗将通过以下方式进行评估 测定肾组织中三磷酸腺苷含量。拟议研究的结果将 有助于我们理解抗癌药物的作用机制 异环磷酰胺引起肾脏损伤。这样的信息可能会导致 可以防止肾脏损伤的治疗方法。

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.