Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts
Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts
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DOI：
10.1215/15228517-2008-090
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发表时间：
2009-06-01
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：
Kitange, Gaspar J.;Carlson, Brett L.;Sarkaria, Jann N.
基于替莫唑胺(TMZ)的治疗是多形性胶质母细胞瘤(GBM)患者的标准治疗方案，而GBM对该药物的耐药性是由DNA修复蛋白O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)调节的。在大约一半的GBM肿瘤中，MGMT的表达被启动子甲基化抑制，临床研究表明，MGMT蛋白水平升高或MGMT启动子甲基化缺失与某些(但不是全部)GBM肿瘤对TMZ的耐药性有关。在本研究中，通过裸鼠连续皮下传代建立了四种GBM异种移植株，并通过裸鼠皮下连续传代，研究了MGMT蛋白表达与肿瘤对TMZ反应的关系。三个未甲基化的MGMT肿瘤基础MGMT蛋白表达升高，但其中只有两个对TMZ治疗耐药(肿瘤GBM43和GBM44)，而另一个(GBM14)的TMZ敏感性水平与单个MGMT高甲基化株(GBM12)相似。在组织培养和动物研究中，TMZ处理在抗病的GBM43和GBM44异种移植系中导致MGMT表达的强烈和持久的诱导，而在GBM14中MGMT的诱导被钝化和缩短。与MGMT诱导的功能意义一致，长期低剂量TMZ方案对GBM43的治疗效果明显低于较短的高剂量方案，而长期给药方案可提高GBM14的存活率。综上所述，在某些MGMT非甲基化肿瘤中，MGMT的表达是动态调节的，在这些肿瘤中，长期给药方案可能无效。神经肿瘤学11,281-291,2009(发表于神经肿瘤学[连载在线]，DOC.D08-00172,2008年10月24日。网址：http://neuro-oncology.dukejournals.org；DOI：10.1215/15228517-10.1215)
Temozolomide (TMZ)-based therapy is the standard of care for patients with glioblastoma multiforme (GBM), and resistance to this drug in GBM is modulated by the DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT). Expression of MGMT is silenced by promoter methylation in approximately half of GBM tumors, and clinical studies have shown that elevated MGMT protein levels or lack of MGMT promoter methylation is associated with TMZ resistance in some, but not all, GBM tumors. In this study, the relationship between MGMT protein expression and tumor response to TMZ was evaluated in four GBM xenograft lines that had been established from patient specimens and maintained by serial subcutaneous passaging in nude mice. Three MGMT unmethylated tumors displayed elevated basal MGMT protein expression, but only two of these were resistant to TMZ therapy (tumors GBM43 and GBM44), while the other (GBM14) displayed a level of TMZ sensitivity that was similar in extent to that seen in a single MGMT hypermethylated line (GBM12). In tissue culture and animal studies, TMZ treatment resulted in robust and prolonged induction of MGMT expression in the resistant GBM43 and GBM44 xenograft lines, while MGMT induction was blunted and abbreviated in GBM14. Consistent with a functional significance of MGMT induction, treatment of GBM43 with a protracted low-dose TMZ regimen was significantly less effective than a shorter high-dose regimen, while survival for GBM14 was improved with the protracted dosing regimen. In conclusion, MGMT expression is dynamically regulated in some MGMT nonmethylated tumors, and in these tumors, protracted dosing regimens may not be effective. Neuro-Oncology 11, 281-291, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00172, October 24, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-090)