Department of Physiology and Pharmacology, The University of Western Ontario, London, Canada.
Can J Physiol Pharmacol. 2011 May;89(5):335-43. doi: 10.1139/y11-028. Epub 2011 May 24.
Ifosfamide-induced nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Our previous cell and rodent models have shown that the antioxidant N-acetylcysteine (NAC), used extensively as an antidote for acetaminophen poisoning, protects renal tubular cells from ifosfamide-induced nephrotoxicity at a clinically relevant concentration. For the use of NAC to be clinically relevant in preventing ifosfamide nephrotoxicity, we must ensure there is no effect of NAC on the antitumor activity of ifosfamide. Common pediatric tumors that are sensitive to ifosfamide, human neuroblastoma SK-N-BE(2) and rhabdomyosarcoma RD114-B cells, received either no pretreatment or pretreatment with 400 µmol/L of NAC, followed by concurrent treatment with NAC and either ifosfamide or the active agent ifosfamide mustard. Ifosfamide mustard significantly decreased the growth of both cancer cell lines in a dose-dependent manner (p < 0.001). The different combined treatments of NAC alone, sodium 2-mercaptoethanesulfonate alone, or NAC plus sodium 2-mercaptoethanesulfonate did not significantly interfere with the tumor cytotoxic effect of ifosfamide mustard. These observations suggest that NAC may improve the risk/benefit ratio of ifosfamide by decreasing ifosfamide-induced nephrotoxicity without interfering with its antitumor effect in cancer cells clinically treated with ifosfamide.
异环磷酰胺诱导的肾毒性是儿童接受化疗时的一种严重不良反应。我们之前的细胞和啮齿动物模型表明，抗氧化剂 N-乙酰半胱氨酸（NAC），广泛用作对乙酰氨基酚中毒的解毒剂，在临床相关浓度下可保护肾小管细胞免受异环磷酰胺诱导的肾毒性。为了使 NAC 在预防异环磷酰胺肾毒性方面具有临床意义，我们必须确保 NAC 对异环磷酰胺的抗肿瘤活性没有影响。对异环磷酰胺敏感的常见儿科肿瘤，人神经母细胞瘤 SK-N-BE(2)和横纹肌肉瘤 RD114-B 细胞，要么未经预处理，要么用 400µmol/L 的 NAC 预处理，然后同时用 NAC 和异环磷酰胺或其活性成分异环磷酰胺芥进行处理。异环磷酰胺芥显著地以剂量依赖的方式降低了两种癌细胞系的生长（p<0.001）。NAC 单独、2-巯基乙磺酸单独或 NAC 加 2-巯基乙磺酸的不同联合处理并没有显著干扰异环磷酰胺芥对肿瘤的细胞毒性作用。这些观察结果表明，NAC 可能通过降低异环磷酰胺诱导的肾毒性，而不干扰临床上用异环磷酰胺治疗的癌症细胞的抗肿瘤作用，从而提高异环磷酰胺的风险/效益比。
