NEPHROTOXICITY OF THE CANCER DRUG IFOSFAMIDE

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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.