Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Pharmacology and Toxicology


Dr. Gideon Koren

Second Advisor

Dr. Michael J. Rieder


Presently, substantially more children diagnosed with cancer survive than ever before. However, powerful cancer chemotherapy is associated with serious drug-induced organ damage, adversely affecting the health and the quality of life of these pediatric cancer survivors. This thesis focuses on a chemotherapeutic agent called ifosfamide, which is commonly used to treat pediatric solid tumours such as rhabdomyosarcoma, neuroblastoma, Wilm’s tumour and soft tissue sarcoma. It has been shown to cause serious renal damage substantially more in younger children (less than 3 years of age) than among older children or adults. This often leads to devastating consequences on the long-term health of children. Previous work from our lab has demonstrated that this agedependent nephrotoxicity is caused by a toxic ifosfamide metabolite produced in the kidney by CYP3A. We found that glutathione depletion enhances renal damage caused by ifosfamide in tubular cells. We sought to develop a therapeutic intervention to protect the kidney from ifosfamide-induced damage. We have selected N-acetylcysteine (NAC) as it has been used extensively and safely to treat acetaminophen overdose in children. Investigating its efficacy, we found that NAC prevents ifosfamide-induced nephrotoxicity in porcine renal proximal tubular cells and in a rat model. The use of NAC in children will be feasible only if it does not interfere with the antitumour effect of ifosfamide. To that end we demonstrated that in relevant cancer cell lines (rhabdomyosarcoma and neuroblastoma), NAC does not affect the cytotoxicity of ifosfamide mustard, the pharmacological active metabolite of ifosfamide. In parallel, we measured the plasma concentrations of NAC in children treated for acetaminophen overdose. The systemic exposure of NAC in these pediatric iii patients produced significantly higher levels as compared to our successful rat model. This indicates that the regular safe dosing schedule of NAC in these young patients may be used to prevent ifosfamide nephrotoxicity. In summary, NAC improves the risk-benefit ratio of ifosfamide, suggesting a novel therapeutic role in preventing nephrotoxicity in children treated with ifosfamide.



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