Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Gideon Koren

Abstract

The chemotherapy drug ifosfamide is used in the treatment of several childhood cancers. While effective, its use in children results in a 30% incidence of nephrotoxicity, and 5% incidence of Fanconi syndrome. This late effect is caused by oxidative damage, generated by chloroacetaldehyde, a toxic metabolite of ifosfamide cytochrome P450-mediated bioactivation in the kidney tubules. N-acetylcysteine has been identified as a promising strategy to mitigate nephrotoxicity through its antioxidant and glutathione stimulating properties. Furthermore, with current use in children for acetaminophen poisoning, its clinical utility is evident. Both cell and animal models have demonstrated n-acetylcysteine’s effectiveness in mitigating ifosfamide kidney toxicity. However, there is no data available to suggest the safe use of n-acetylcysteine with respect to maintenance of ifosfamide’s chemotherapeutic integrity. There is also a lack of information suggesting that the current dose for acetaminophen overdose will be sufficient for the alternative indication of renal protection. To address this gap in knowledge, which is critical in moving forward with the use of n-acetylcysteine in a clinical setting, herein I describe three studies, which focus on the translational pharmacokinetics of n-acetylcysteine, as well as its effect on the efficacy of ifosfamide. Using a comparison of our therapeutically effective rodent model to children receiving the 21-hour intravenous dose of n-acetylcysteine for acetaminophen overdose, we were able to demonstrate similar systemic exposures are achieved in both groups. This corroborates that the dose currently used in children is an excellent choice for renal protection. To demonstrate the impact of n-acetylcysteine on the antitumor efficacy of ifosfamide, we evaluated the combination of n-acetylcysteine and ifosfamide mustard, the active antineoplastic agent in vitro and n-acetylcysteine and ifosfamide in a mouse xenograft model. Our investigations provide evidence to suggest n-acetylcysteine does not interfere with ifosfamide activity, further supporting its safe use. Based on existing evidence, including that presented in this thesis, we have developed clinical protocol recommendations, for the safe use of n-acetylcysteine for children who present with renal toxicity due to ifosfamide. I also detail a randomized prospective double-blinded study designed to assess the effectiveness of n-acetylcysteine as a prophylactic strategy, in a control fashion.

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