Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models
Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models
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DOI：
10.1093/neuonc/not010
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发表时间：
2013-06-01
期刊：
影响因子：
15.9
通讯作者：
Sarkaria, Jann N.
中科院分区：
文献类型：
--
作者：
Cen, Ling;Carlson, Brett L.;Sarkaria, Jann N.
替莫唑胺（TMZ）是治疗多形性胶质母细胞瘤（GBM）的重要化疗药物，但其最佳给药方案尚不明确。在颅内治疗评价模型中，比较了7例原发性GBM移植瘤的不同临床相关给药方案的疗效。（TMZ每日MF，在4个O-6-DNA甲基鸟嘌呤-甲基转移酶（MGMT）启动子高甲基化株系（GBM 12）中，而标准治疗（TMZ每日MF，每4周1次）在3个MGMT未甲基化细胞系中的2个（GBM 14和GBM 43）中提供了优于安慰剂治疗组的上级存活率，并且没有甲基化细胞系。在比较GBM 12、GBM 14和GBM 43颅内标本时，与安慰剂相比，用长期TMZ治疗的GBM 14和GBM 43小鼠的MGMT水平显著升高。类似地，在GBM 14侧腹异种移植物中的获得性TMZ抗性的第二模型中发现高MGMT，并且通过用MGMT抑制剂0 -6-苄基鸟嘌呤处理在体外逆转抗性，证明了该品系中MGMT过表达与TMZ抗性之间的机制联系。此外，在基因表达数据的分析中，亲本和TMZ耐药GBM 14的比较证明了在细胞周期的S、G2和M期内细胞周期控制的功能本体和DNA损伤checkpoints.Across研究的7个肿瘤模型中，长期和标准TMZ方案之间没有一致的差异。长期TMZ方案的疗效可能因诱导MGMT表达而限制在MGMT未甲基化肿瘤亚组中。
Temozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear.The efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model.Protracted TMZ therapy (TMZ daily MF, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O-6-DNA methylguanine-methyltransferase (MGMT) promoter hypermethylated lines (GBM12) and none of the 3 MGMT unmethylated lines, while standard therapy (TMZ daily MF, 1 wk every 4) provided superior survival to the placebo-treated group in 2 of 3 MGMT unmethylated lines (GBM14 and GBM43) and none of the methylated lines. In comparing GBM12, GBM14, and GBM43 intracranial specimens, both GBM14 and GBM43 mice treated with protracted TMZ had a significant elevation in MGMT levels compared with placebo. Similarly, high MGMT was found in a second model of acquired TMZ resistance in GBM14 flank xenografts, and resistance was reversed in vitro by treatment with the MGMT inhibitor O-6-benzylguanine, demonstrating a mechanistic link between MGMT overexpression and TMZ resistance in this line. Additionally, in an analysis of gene expression data, comparison of parental and TMZ-resistant GBM14 demonstrated enrichment of functional ontologies for cell cycle control within the S, G2, and M phases of the cell cycle and DNA damage checkpoints.Across the 7 tumor models studied, there was no consistent difference between protracted and standard TMZ regimens. The efficacy of protracted TMZ regimens may be limited in a subset of MGMT unmethylated tumors by induction of MGMT expression.