Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma.
Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma.
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DOI：
10.18632/oncotarget.3504
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发表时间：
2015-04-30
期刊：
影响因子：
--
通讯作者：
Tweddle DA
中科院分区：
文献类型：
--
作者：
Chen L;Rousseau RF;Middleton SA;Nichols GL;Newell DR;Lunec J;Tweddle DA
神经母细胞瘤主要是p53野生型（wt）肿瘤，MDM 2-p53拮抗剂为神经母细胞瘤患者提供了一种新的治疗策略。RG 7388（Roche）目前正在成人中进行早期临床评价。本研究评估了RG 7388作为单药以及与目前用于治疗一组神经母细胞瘤细胞系中神经母细胞瘤的化疗药物联合使用的疗效。在不同MYCN、MDM 2和p14 ARF状态的21个p53-wt和突变型神经母细胞瘤细胞系以及MYCN可调节的Tet 21 N细胞中测定了RG 7388 GI 50浓度。反应的主要决定因素是wt p53的存在，总体而言，p53-wt与突变细胞系的RG 7388 GI 50浓度差异>200倍。Tet 21 N MYCN+细胞对RG 7388的敏感性显著高于MYCN−细胞。在5种p53-wt神经母细胞瘤细胞系中使用中效分析，RG 7388与顺铂、多柔比星、拓扑替康、替莫唑胺和白消安的选定组合具有协同作用。此外，联合治疗导致细胞凋亡增加，与单独使用任一种药物相比，caspase-3/7活性更高。这些数据表明，RG 7388对p53-wt神经母细胞瘤细胞具有高度效力，并强烈支持其作为高风险神经母细胞瘤和wt p53患者的新型疗法的进一步评价，以潜在地改善生存和/或降低毒性。
Neuroblastoma is a predominantly p53 wild-type (wt) tumour and MDM2-p53 antagonists offer a novel therapeutic strategy for neuroblastoma patients. RG7388 (Roche) is currently undergoing early phase clinical evaluation in adults. This study assessed the efficacy of RG7388 as a single-agent and in combination with chemotherapies currently used to treat neuroblastoma in a panel of neuroblastoma cell lines. RG7388 GI50 concentrations were determined in 21 p53-wt and mutant neuroblastoma cell lines of varying MYCN, MDM2 and p14ARF status, together with MYCN-regulatable Tet21N cells. The primary determinant of response was the presence of wt p53, and overall there was a >200-fold difference in RG7388 GI50 concentrations for p53-wt versus mutant cell lines. Tet21N MYCN+ cells were significantly more sensitive to RG7388 compared with MYCN− cells. Using median-effect analysis in 5 p53-wt neuroblastoma cell lines, selected combinations of RG7388 with cisplatin, doxorubicin, topotecan, temozolomide and busulfan were synergistic. Furthermore, combination treatments led to increased apoptosis, as evident by higher caspase-3/7 activity compared to either agent alone. These data show that RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity.
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影响因子：
9
作者：
通讯作者：
--
影响因子：
3.8
作者：
Ohnstad HO;Paulsen EB;Noordhuis P;Berg M;Lothe RA;Vassilev LT;Myklebost O
通讯作者：
Myklebost O
影响因子：
8
作者：
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通讯作者：
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影响因子：
8.8
作者：
Chen, L.;Zhao, Y.;Halliday, G. C.;Berry, P.;Rousseau, R. F.;Middleton, S. A.;Nichols, G. L.;Del Bello, F.;Piergentili, A.;Newell, D. R.;Lunec, J.;Tweddle, D. A.
通讯作者：
Tweddle, D. A.
影响因子：
7.3
作者：
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通讯作者：
Lunec, John