title: N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models.
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 mm(3) 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 mm(3), 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.
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Muldoon
authors.forename: Y Jeffrey
authors.initials: YJ
authors.lastname: Wu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pagel
authors.forename: Edward A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000473:pathology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011923:Rats, Nude
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002945:Cisplatin; D000111:Acetylcysteine