Cancer 2013(8)-31

 

The Effects of N-acetylcysteine on ifosfamide efficacy in a mouse xenograft model.

Anticancer Res. 2012 Sep;32(9):3791-8.

Hanly L, Figueredo R, Rieder MJ, Koropatnick J, Koren G.

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.

 

Abstract

BACKGROUND/AIM: Nephrotoxicity is observed in 30% of children treated with ifosfamide. We have shown that n-acetylcysteine (NAC) successfully mitigates nephrotoxicity of ifosfamide in cell and rodent models. However, before this treatment is evaluated clinically, it must be established that NAC does not interfere with the efficacy of ifosfamide.

MATERIALS AND METHODS: Mice implanted with Ewing’s sarcoma tumours received the following treatments: saline, ifosfamide, ifosfamide + NAC concurrently, pre-treatment with NAC + ifosfamide, or NAC alone.

RESULTS: Median volumes of EW-7 tumour xenografts in mice treated with ifosfamide (n=8), ifosfamide with concurrent NAC therapy (n=7), and NAC pre-treatment (n=6) (p<0.05) were significantly reduced compared to median tumour volumes of control mice (n=6). None of the NAC treatments affected ifosfamide-mediated reduction in tumour volumes.

CONCLUSION: NAC does not interfere with the efficacy of ifosfamide in a EW-7 xenograft model. These results support the clinical evaluation of NAC as a strategy against ifosfamide-induced nephrotoxicity in children.

PMID: 22993321

 

Supplement:

Chemotherapeutics play an important role in the treatment of cancer. While they provide major health benefits including increased survival, they are also responsible for adverse effects including long-term organ damage. Nephrotoxicity and acute kidney injury are well-studied side effects of the drug ifosfamide when used in the treatment of cancer in children.

To date, preclinical research has elucidated potential mechanisms of ifosfamide kidney toxicity, as well as identified promising preventative and treatment options, including n-acetylcysteine (NAC). NAC, which is currently used in children for acetaminophen overdose, protects against ifosfamide kidney toxicity in cell and animal models. It has also been protective as a rescue strategy in 3 children presenting with kidney dysfunction before or during ifosfamide treatment.

While there is growing interest in preventing such adverse outcomes of cancer therapy, it is imperative that any new treatments will not interfere with efficacy of the chemotherapy. That is to say that the integrity of ifosfamide treatment must be maintained if NAC can to be used clinically.

Given the importance of this information to the safe clinical use of NAC, our research investigated the potential effects of NAC on ifosfamide’s ability to treat cancer in a Ewing’s sarcoma mouse xenograft model. In this xenograft model, ifosfamide was able to reduce tumor volumes as compared to untreated control mice. Most importantly, the ability of ifosfamide to reduce tumor volumes was not impaired when mice were also treated with NAC, either concurrently or as a pretreatment, indicating NAC does not interfere with ifosfamide treatment.

These results are important as they suggest that NAC can be used safely as an adjunct to chemotherapy, in an effort to protect against the negative effects ifosfamide has on the kidney’s. This research highlights the need for clinical evaluation of NAC in children treated with ifosfamide in order to increase both their quality of care and quality of life.

 

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