RADIOSENSITIZING EFFECTS OF TEMOZOLOMIDE OBSERVED IN VIVO ONLY IN A SUBSET OF O6-METHYLGUANINE-DNA METHYLTRANSFERASE METHYLATED GLIOBLASTOMA MULTIFORME XENOGRAFTS
RADIOSENSITIZING EFFECTS OF TEMOZOLOMIDE OBSERVED IN VIVO ONLY IN A SUBSET OF O6-METHYLGUANINE-DNA METHYLTRANSFERASE METHYLATED GLIOBLASTOMA MULTIFORME XENOGRAFTS
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DOI：
10.1016/j.ijrobp.2009.04.026
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发表时间：
2009-09-01
影响因子：
7
通讯作者：
Sarkaria, Jann N.
中科院分区：
文献类型：
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作者：
Carlson, Brett L.;Grogan, Patrick T.;Sarkaria, Jann N.
目的：同时替莫唑胺（TMZ）和放射治疗（RT），随后辅助TMZ是多形性胶质母细胞瘤（GBM）患者的标准治疗，尽管同时与辅助TMZ的相对贡献尚不清楚。在这项研究中，TMZ/RT的疗效进行了测试与面板的20个主要GBM xenografts.Methods和材料：小鼠颅内异种移植治疗TMZ，RT，TMZ/RT，或安慰剂。结果：TMZ治疗后，O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）甲基化肿瘤的中位生存率显著高于未甲基化肿瘤（中位生存率分别为3.6 vs. 1.5; p = 0.008）或TMZ/RT（分别为5.7 vs. 2.3; p = 0.001），但不是单独RT（1.7 vs. 1.6; p = 0.47）。在方差分析中，MGMT甲基化状态和p53突变状态与治疗反应显著相关。当我们分析了联合治疗带来的额外生存获益时，只有一个亚组（11例中的5例）的MGMT甲基化肿瘤从联合治疗中获得了实质性的额外获益，而MGMT未甲基化肿瘤则没有。与TMZ的真实放射增敏作用一致，RT（第1周）后TMZ（第2周）的序贯治疗证明效果显著低于TMZ后RT或同时TMZ/RT（存活率分别为4.0、9.6和12.9; p < 0.0001）。TMZ和RT的同时治疗仅在MGMT甲基化肿瘤的子集中提供显著的生存益处，并且相对于RT和TMZ的顺序施用提供了上级抗肿瘤活性。(c)2009 Elsevier Inc.
Purpose: Concurrent temozolomide (TMZ) and radiation therapy (RT) followed by adjuvant TMZ is standard treatment for patients with glioblastoma multiforme (GBM), although the relative contribution of concurrent versus adjuvant TMZ is unknown. In this study, the efficacy of TMZ/RT was tested with a panel of 20 primary GBM xenografts.Methods and Materials: Mice with intracranial xenografts were treated with TMZ, RT, TMZ/RT, or placebo. Survival ratio for a given treatment/line was defined as the ratio of median survival for treatment vs. placebo.Results: The median survival ratio was significantly higher for O6-methylguanine-DNA methyltransferase (MGMT) methylated tumors versus ummethylated tumors following treatment with TMZ (median survival ratio, 3.6 vs. 1.5, respectively; p = 0.008) or TMZ/RT (5.7 vs. 2.3, respectively; p = 0.001) but not RT alone (1.7 vs. 1.6; p = 0.47). In an analysis of variance, MGMT methylation status and p53 mutation status were significantly associated with treatment response. When we analyzed the additional survival benefit conferred specifically by combined therapy, only a subset (5 of 11) of MGMT methylated tumors derived substantial additional benefit from combined therapy, while none of the MGMT unmethylated tumors did. Consistent with a true radiosensitizing effect of TMZ, sequential treatment in which RT (week 1) was followed by TMZ (week 2) proved significantly less effective than TMZ followed by RT or concurrent TMZ/RT (survival ratios of 4.0, 9.6 and 12.9, respectively; p < 0.0001).Conclusions: Concurrent treatment with TMZ and RT provides significant survival benefit only in a subset of MGMT methylated tumors and provides superior antitumor activity relative to sequential administration of RT and TMZ. (c) 2009 Elsevier Inc.