Abstract 839: N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models
Authors: Muldoon Leslie L. , Wu Y. Jeffrey , Pagel Michael A. , Beeson Kathleen A. , Neuwelt Edward A. 
Published: May 2015

Abstract
PURPOSE. Cisplatin chemotherapy is used in the treatment of many pediatric cancers, but has significant toxicities that impact patient quality of life. Decreasing oxidative damage with the anti-oxidant agent N-acetylcysteine (NAC) can reduce cisplatin side effects; however its use is limited by concerns about decreased anti-tumor efficacy. This study evaluated the effect of the timing of NAC on cisplatin efficacy in vitro and in rat models of human pediatric cancers. METHODS. Female athymic nude 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 (1000 mg/kg IV) 30 min before or 4 h after cisplatin treatment. Blood urea nitrogen (BUN) and tumor volumes were measured. Viability and apoptosis were assessed in vitro in both cell types. RESULTS. NAC was protective against cisplatin toxicity in both SK-N-AS and D283-MED cells in vitro if added within 2 h after chemotherapy. Untreated SK-N-AS neuroblastoma subcutaneous tumor volumes increased by 17.7 ± 4.9 fold over 2 weeks, with final tumor weight of 4.3 ± 1.6 g. Cisplatin decreased relative tumor growth to 6.4 ± 2.5 fold over baseline (P&lt;0.0001) with final tumor weight of 1.7 ± 0.9 g. Pretreatment with NAC significantly decreased cisplatin efficacy (tumor volume 15.0 ± 4.8 fold over baseline, not different from untreated control), while 4 h delayed NAC did not significantly affect cisplatin anti-tumor effects (relative tumor volume 6.8 ± 2.0 fold baseline, P&lt;0.001). For the 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). When NAC was given prior to cisplatin tumor volume did not differ from untreated control (13.3 ± 23.1 mm3, P = 0.060). Delayed NAC was not significantly different than cisplatin alone (tumor volume 6.8 ± 8.1 mm3, P = 0.014 versus control). Two doses of cisplatin increased BUN levels to 57.3 ±19.9 mg/dL at 7 days after treatment, compared to 18.9 ± 2.0 in untreated control rats (P&lt;0.001). Both pretreatment or delayed treatment with NAC decreased BUN compared to cisplatin alone (25.3 ± 6.8 and 27.9 ± 7.5 respectively, P&lt;0.001). We conclude that NAC protects against kidney toxicity without impacting cisplatin therapy, if delayed until 4 h after chemotherapy. These data support a clinical trial of delayed NAC to reduce chemotherapy toxicities in children with cancer.
Citation Format: Leslie L. Muldoon, Y. Jeffrey Wu, Michael A. Pagel, Kathleen A. Beeson, Edward A. Neuwelt. N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 839. doi:10.1158/1538-7445.AM2014-839