title: Comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells.
abstract: Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde contributes to this nephrotoxicity. The present study examined the effects of chloroacetaldehyde and acrolein, another ifosfamide metabolite, on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde- and acrolein-induced renal cell injury was also assessed. Chloroacetaldehyde and acrolein (25-200 M) produced dose-dependent declines in neutral red dye uptake, glucose transport and glutathione content. Chloroacetaldehyde was a more potent toxin than acrolein. Pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of both chloroacetaldehyde and acrolein while co-administration of mesna or amifostine prevented metabolite toxicity. These results support the hypothesis that chloroacetaldehyde is responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity.
authors.affiliation: Departments of Pediatrics (E.L.Z., J.E.S.) and Biochemistry (M.T.), School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14214, Buffalo, New York, USA.
authors.forename: Emad L
authors.initials: EL
authors.lastname: Zaki
authors.forename: James E
authors.initials: JE
authors.lastname: Springate
authors.forename: Mary
authors.initials: M
authors.lastname: Taub
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D000171:Acrolein / Q000494:pharmacology; D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007069:Ifosfamide / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects*; D015080:Mesna / Q000494:pharmacology*; D009499:Neutral Red; D011817:Rabbits
chemical_list: D000970:Antineoplastic Agents; D009499:Neutral Red; D000171:Acrolein; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D005947:Glucose; D004999:Amifostine; D015080:Mesna; D007069:Ifosfamide