IFN-beta sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression.
IFN-beta sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression.
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DOI：
10.1158/1535-7163.mct-08-0806
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发表时间：
2008-12
影响因子：
5.7
通讯作者：
Davidoff AM
中科院分区：
文献类型：
--
作者：
Rosati SF;Williams RF;Nunnally LC;McGee MC;Sims TL;Tracey L;Zhou J;Fan M;Ng CY;Nathwani AC;Stewart CF;Pfeffer LM;Davidoff AM
虽然替莫唑胺（TMZ）已显示出对神经母细胞瘤的临床活性，但这种活性可能受到DNA修复酶O 6-甲基鸟嘌呤DNA甲基转移酶（MGMT）的限制。我们假设干扰素-β（IFN-β）可以通过下调MGMT表达的能力使神经母细胞瘤细胞对TMZ的细胞毒性作用敏感。研究了IFN-β和TMZ单独或联合处理的三种神经母细胞瘤细胞系的体外增殖。在局部和播散性神经母细胞瘤异种移植模型中使用单一药剂和组合疗法评估抗肿瘤活性，其中通过肝靶向AAV介导的方法建立IFN-β的连续递送。还测量了MGMT表达。发现两种神经母细胞瘤细胞系（NB-1691，SK-N-AS）具有高基线水平的MGMT表达，而第三种细胞系（CHLA-255）具有低水平。TMZ对MGMT高表达的神经母细胞瘤细胞株体外增殖无明显影响，而IFN-β预处理可显著降低MGMT表达和细胞数。在体内，与未治疗的对照小鼠和单独用任一种药剂治疗的小鼠相比，用IFN-β和TMZ组合治疗的荷瘤小鼠在局部和播散性疾病模型中具有较低的MGMT表达和显著降低的NB-1691肿瘤负荷。IFN-β似乎通过减弱MGMT表达使神经母细胞瘤细胞对TMZ的细胞毒性作用敏感。因此，IFN-β和TMZ可能是治疗儿童这种困难疾病的有效组合。
Although temozolomide (TMZ) has shown clinical activity against neuroblastoma, this activity is likely limited by the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT). We hypothesized that interferon-beta (IFN-β) could sensitize neuroblastoma cells to the cytotoxic effects of TMZ through its ability to down regulate MGMT expression. In vitro proliferation of three neuroblastoma cell lines treated with IFN-β and TMZ alone, or in combination, was examined. Anti-tumor activity was assessed in both localized and disseminated neuroblastoma xenograft models using single agent and combination therapy, with continuous delivery of IFN-β being established by a liver-targeted AAV-mediated approach. MGMT expression was also measured. Two neuroblastoma cell lines (NB-1691, SK-N-AS) were found to have high baseline levels of MGMT expression while a third cell line (CHLA-255) had low levels. TMZ had little effect on in vitro proliferation of the neuroblastoma cell lines with high MGMT expression, but pretreatment with IFN-β significantly decreased MGMT expression and cell counts. In vivo, tumor bearing mice treated with the combination of IFN-β and TMZ had lower MGMT expression and a significantly reduced NB-1691 tumor burden in models of localized and disseminated disease when compared to untreated control mice and those treated with either agent alone. IFN-β appears to sensitize neuroblastoma cells to the cytotoxic effects of TMZ through attenuation of MGMT expression. Thus, IFN-β and TMZ may be a useful combination for treating children with this difficult disease.