Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models.
Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models.
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DOI：
10.1038/sj.bjc.6605927
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发表时间：
2010-10-26
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
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替莫唑胺(TMZ)和伊立替康联合应用是治疗复发的神经母细胞瘤患者的一种方案。O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)可能在TMZ抗性中起作用。利用神经母细胞瘤临床前模型，我们确定了O6-苄基鸟嘌呤(O6-BG)对MGMT的抑制是否能增强TMZ和伊立替康的抗肿瘤活性。用基于荧光的细胞活力分析法(DIMSCAN)检测了在O6-BG存在或不存在的情况下，TMZ和伊立替康单独或联合使用对5种神经母细胞瘤细胞系的细胞毒作用。测定了三种神经母细胞瘤异种移植模型的抗肿瘤活性。在10个细胞株中，有9个细胞株表达MGMT基因和蛋白。用25 μMO6-BG处理细胞后，在5个受试细胞系中，有4个细胞株的MGMT蛋白表达减少，细胞毒作用增强，最高可达0.3~1.4logS。曲美他嗪(25 mg kg−1，每天5天，每3周1次，共4个周期)不能显著提高小鼠的存活率，而伊立替康(7.5 mg kg−1，每天1次)能显著提高3种异种移植模型的存活率(P<；0.0001)。O6-BG和/或TMZ与伊立替康联合应用可进一步提高存活率。我们的体外和体内研究结果表明，在复发性神经母细胞瘤中，伊立替康促进伊立替康和TMZ的活性。MGMT的抑制剂需要进一步研究，以增强包括TMZ在内的方案的活性。
The combination of temozolomide (TMZ) and irinotecan is a regimen used in neuroblastoma patients with recurrent disease. O6-methylguanine-DNA methyltransferase (MGMT) may have a function in resistance to TMZ. Using neuroblastoma pre-clinical models, we determined whether the inhibition of MGMT by O6-benzylguanine (O6-BG) could enhance the anti-tumour activity of TMZ and irinotecan. The cytotoxicity of TMZ and irinotecan, either alone or in combination, was measured in five neuroblastoma cell lines in the presence or absence of O6-BG with a fluorescence-based cell viability assay (DIMSCAN). Anti-tumour activity was measured in three neuroblastoma xenograft models. MGMT mRNA and protein were expressed in 9 out of 10 examined cell lines. Pretreatment of cells with 25 μM O6-BG decreased MGMT protein expression and enhanced The TMZ cytotoxicity by up to 0.3–1.4 logs in four out of five tested cell lines. TMZ (25 mg kg−1 per day for 5 days every 3 weeks for four cycles) did not significantly improve mice survival, whereas the same schedule of irinotecan (7.5 mg kg−1 per day) significantly improved survival (P<0.0001) in all three xenograft models. Combining O6-BG and/or TMZ with irinotecan further enhanced survival. Our in vitro and in vivo findings suggest that irinotecan drives the activity of irinotecan and TMZ in recurrent neuroblastoma. Inhibitors of MGMT warrant further investigation for enhancing the activity of regimens that include TMZ.
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影响因子：
3.2
作者：
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通讯作者：
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影响因子：
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