Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity
Sodium thiosulfate administered six hours after cisplatin does not compromise antineuroblastoma activity
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DOI：
10.1158/1078-0432.ccr-06-2289
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发表时间：
2008-01-15
影响因子：
11.5
通讯作者：
Reynolds, C. Patrick
中科院分区：
文献类型：
--
作者：
Harned, Theresa M.;Kalous, Ondrej;Reynolds, C. Patrick
目的：我们确定在顺铂后6小时给予潜在的耳保护剂硫代硫酸钠（STS），是否不会降低顺铂在体外对人神经母细胞瘤细胞系（包括顺铂耐药细胞系）和体内异种神经母细胞瘤移植中的抗神经母细胞瘤活性。实验设计：在标准细胞培养条件下（20% O-2）和生理性缺氧条件下（2% O-2），我们在6种神经母细胞瘤细胞系中测定顺铂加STS或不加STS后0或6小时的抗神经母细胞瘤活性。采用DIMSCAN荧光/数字成像显微镜法测定药物细胞毒性。顺铂联合STS的体内研究采用人神经母细胞瘤皮下异种移植模型（SMS-SAN）在胸腺nu/nu小鼠中进行。结果：顺铂联合STS对神经母细胞瘤细胞有明显的抗顺铂细胞毒性作用。然而，当首先给予顺铂并在6小时后暴露STS时，未观察到对顺铂细胞毒性的影响。在nu/nu小鼠皮下神经母细胞瘤异种移植模型中，与对照组或同时接受顺铂+ STS治疗的小鼠相比，单独接受顺铂或6 h顺铂+ STS治疗的小鼠无进展生存率显著提高（P < 0.03）。单独顺铂组与6 h后顺铂联合STS组的预后无统计学差异（P = 0.9）。结论：这些临床前数据表明，顺铂后6小时使用STS进行耳保护不太可能损害顺铂的抗神经母细胞瘤活性。
Purpose: We determined if the potentially otoprotective agent sodium thiosulfate (STS) could be given 6 h after cisplatin without diminishing the antineuroblastoma activity of cisplatin in human neuroblastoma cell lines in vitro (including cisplatin-resistant cell lines) and in neuroblastoma xenografts in vivo.Experimental Design: We determined the antineuroblastoma activity of cisplatin with or without the addition of STS at 0 or 6 h after cisplatin in six neuroblastoma cell lines, both in standard cell culture conditions (20% O-2) and in physiologic hypoxia (2% O-2). Drug cytotoxicity was measured using the DIMSCAN fluorescence/digital imaging microscopy assay. In vivo studies of cisplatin combined with STS used a human neuroblastoma subcutaneous xenograft model (SMS-SAN) in athymic nu/nu mice.Results: A significant protection against cisplatin cytotoxicity was seen when the neuroblastoma cells were exposed to cisplatin directly combined with STS. However, when cisplatin was given first and STS exposure occurred 6 h later, no effect on cisplatin cytotoxicity was observed. In a subcutaneous neuroblastoma xenograft model in nu/nu mice, mice receiving cisplatin alone or cisplatin + STS at 6 h had significantly better progression-free survival rates (P < 0.03) compared with controls or mice treated with cisplatin + STS concurrently. There was no statistically significant difference in outcomes between mice treated with cisplatin alone and the group treated with cisplatin followed by STS 6 h later (P = 0.9).Conclusion: These preclinical data suggest that the use of STS 6 h after cisplatin for otoprotection is unlikely to compromise the antineuroblastoma activity of cisplatin.