Use of ifosfamide, an isomer of cylophosphamide with demonstrated activity against a spectrum of pediatric and adult tumors, has been limited by neurotoxic and nephrotoxic side effects. We have obtained preliminary evidence that chloroacetaldehyde, a metabolite of ifosfamide and of industrial toxins such as vinyl chloride, attains high concentrations in blood (5-50 mu M) and urine (100- 1000 mu M). This suggests that chloroacetaldehyde may be a causative factor in the development of the neurotoxicity and nephrotoxicity in patients being treated with ifosfamide, and may contribute to the bladder toxicity of both ifosfamide and cyclophosphamide. We propose to test this idea in rats and in childhood cancer patients who are receiving ifosfamide as part of their planned therapy. The long-range goal is to devise methods that will reduce the risk of adverse clinical effects associated with ifosfamide therapy. The immediate objectives are (1) to determine if and to what extent chloroacetaldehyde contributes to toxic effects on the central nervous system, kidney, and bladder; (2) to identify the risk factors that might lead to increased concentrations of chloroacetaldehyde in blood and urine (e.g., schedules of administration, effects of prior therapy, drug-drug interactions); and (3) to determine if mesna and N-acetyl-L- cysteine can remove chloroacetaldehyde from the urine and blood, respectively. The results of this work should allow us to identify clinical situations in which there is an increased risk of ifosfamide-induced toxicity and perhaps to find a pharmacologic basis for ameliorating such toxicity. Information from these studies will increase our understanding of the pharmacology and toxicity of chloroacetaldehyde in relationship to other anticancer agents and industrial toxins.
