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N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Decreasing oxidative damage with the antioxidant agent N-acetylcysteine (NAC) can block the side effects of chemotherapy, but may diminish anti-tumor efficacy. We tested the potential for interactions of high dose NAC against a minimally effective cisplatin chemotherapy regimen in rat models of human pediatric cancers. Athymic rats received subcutaneous implantation of human SK-N-AS neuroblastoma cells or intra-cerebellar implantation of human D283-MED medulloblastoma cells. Rats were untreated or treated with cisplatin (3 or 4 mg/kg IV) with or without NAC (1,000 mg/kg IV) 30 min before or 4 h after cisplatin treatment. Blood urea nitrogen (BUN) and tumor volumes were measured. Cisplatin decreased the growth of SK-N-AS neuroblastoma subcutaneous tumors from 17.7 ± 4.9 to 6.4 ± 2.5 fold over baseline 2 weeks after treatment (P < 0.001). Pretreatment with NAC decreased cisplatin efficacy, while 4 h delayed NAC did not significantly affect cisplatin anti-tumor effects (relative tumor volume 6.8 ± 2.0 fold baseline, P < 0.001). In D283-MED medulloblastoma brain tumors, cisplatin decreased final tumor volume to 3.9 ± 2.3 mm3 compared to untreated tumor volume of 45.9 ± 38.7 (P = 0.008). Delayed NAC did not significantly alter cisplatin efficacy (tumor volume 6.8 ± 8.1 mm3, P = 0.014 versus control). Cisplatin was minimally nephrotoxic in these models. NAC decreased cisplatin-induced elevations in BUN (P < 0.02). NAC chemoprotection did not alter cisplatin therapy, if delayed until 4 h after chemotherapy. These data support a Phase I/II clinical trial of delayed NAC to reduce ototoxicity in children with localized pediatric cancers.

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Abbreviations

BUN:

Blood urea nitrogen

NAC:

N-acetylcysteine

ROS:

Reactive oxygen species

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Acknowledgements

Thank you to Ms. Kathleen Beeson for her excellent technical assistance. This work was supported by the National Institutes of Health National Cancer Institute [grant CA137488] and National Institute of Neurological Diseases and Stroke [grant NS44687]; a Veterans Administration Merit Review grant; and the Walter S. and Lucienne Driskill Foundation, all to EAN.

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Authors and Affiliations

  1. Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Leslie L. Muldoon, Y. Jeffrey Wu & Edward A. Neuwelt

  2. Department of Cell, Developmental and Cancer Biology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Leslie L. Muldoon

  3. Department of Neurosurgery, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Edward A. Neuwelt

  4. Veterans Administration Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA

    Michael A. Pagel & Edward A. Neuwelt

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  1. Leslie L. Muldoon
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  2. Y. Jeffrey Wu
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  3. Michael A. Pagel
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  4. Edward A. Neuwelt
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Correspondence to Edward A. Neuwelt.

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Muldoon, L.L., Wu, Y.J., Pagel, M.A. et al. N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models. J Neurooncol 121, 433–440 (2015). https://doi.org/10.1007/s11060-014-1657-1

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  • DOI: https://doi.org/10.1007/s11060-014-1657-1

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