Muldoon Leslie L, Wu Y Jeffrey, Pagel Michael A, Neuwelt Edward A
Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
J Neurooncol. 2015 Feb;121(3):433-40. doi: 10.1007/s11060-014-1657-1. Epub 2014 Nov 21.
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.
使用抗氧化剂N - 乙酰半胱氨酸（NAC）减少氧化损伤可阻断化疗的副作用，但可能会降低抗肿瘤疗效。我们在人类小儿癌症大鼠模型中测试了高剂量NAC与最低有效顺铂化疗方案相互作用的可能性。无胸腺大鼠皮下植入人SK - N - AS神经母细胞瘤细胞或小脑内植入人D283 - MED髓母细胞瘤细胞。大鼠未接受治疗，或在顺铂治疗前30分钟或治疗后4小时接受顺铂（3或4mg/kg静脉注射），加或不加NAC（1000mg/kg静脉注射）。测量血尿素氮（BUN）和肿瘤体积。顺铂使SK - N - AS神经母细胞瘤皮下肿瘤的生长在治疗后2周从基线的17.7±4.9倍降至6.4±2.5倍（P < 0.001）。NAC预处理降低了顺铂疗效，而延迟4小时给予NAC对顺铂的抗肿瘤作用无显著影响（相对肿瘤体积为基线的6.8±2.0倍，P < 0.001）。在D283 - MED髓母细胞瘤脑肿瘤中，顺铂使最终肿瘤体积降至3.9±2.3mm³，而未治疗的肿瘤体积为45.9±38.7（P = 0.008）。延迟给予NAC对顺铂疗效无显著改变（肿瘤体积6.8±8.1mm³，与对照组相比P = 0.014）。在这些模型中，顺铂的肾毒性极小。NAC降低了顺铂诱导BUN的升高（P < 0.02）。如果将NAC的化学保护作用延迟至化疗后4小时，则不会改变顺铂治疗效果。这些数据支持进行一项I/II期临床试验，以评估延迟给予NAC对局部小儿癌症患儿耳毒性的降低作用。
