O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells
O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells
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DOI：
10.1111/j.1471-4159.2005.03583.x
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Weller, M
中科院分区：
文献类型：
--
作者：
Hermisson, M;Klumpp, A;Weller, M
替莫唑胺（TMZ）是一种甲基化剂，当在胶质母细胞瘤的一线治疗中在放射治疗期间和之后施用时，其延长存活，并且其在复发性疾病中也具有显著活性。O-6-甲基鸟嘌呤DNA甲基转移酶（MGMT）是一种DNA修复酶，在肿瘤细胞对O-6-烷化剂化疗的耐药性中起作用。使用一组12个人胶质瘤细胞系，我们在这里定义了敏感性TMZ在急性细胞毒性和克隆形成的生存试验有关的MGMT，错配修复和p53状态和它的调制地塞米松，辐射和BCL-X-L。我们发现MGMT表达水平是人脑胶质瘤细胞TMZ敏感性的主要预测因子。TMZ暴露后MGMT活性和克隆存活率高度相关（p < 0.0001，r（2）= 0.92）。相比之下，TMZ暴露后的克隆存活率与错配修复蛋白mutS同源物2、mutS同源物6或减数分裂后分离增加2的表达水平无关。MGMT抑制剂O-6-苄基鸟嘌呤使MGMT阳性胶质瘤细胞对TMZ敏感，而MGMT基因转移到MGMT阴性细胞中赋予保护作用。抗凋亡BCL-X-L蛋白减弱TMZ在MGMT阴性LNT-229细胞中的细胞毒性，但在MGMT阳性LN-18细胞中不减弱。电离辐射（4戈伊）和临床相关浓度的地塞米松均不调节MGMT活性或TMZ敏感性。p53野生型功能的消除强烈减弱TMZ细胞毒性。相反，设计用于稳定p53野生型构象的p53模拟剂使胶质瘤细胞对TMZ细胞毒性敏感。总的来说，这些结果表明，MGMT表达和p53状态的确定将有助于确定胶质瘤患者谁会或不会响应TMZ。
Temozolomide (TMZ) is a methylating agent which prolongs survival when administered during and after radiotherapy in the first-line treatment of glioblastoma and which also has significant activity in recurrent disease. O-6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme attributed a role in cancer cell resistance to O-6-alkylating agent-based chemotherapy. Using a panel of 12 human glioma cell lines, we here defined the sensitivity to TMZ in acute cytotoxicity and clonogenic survival assays in relation to MGMT, mismatch repair and p53 status and its modulation by dexamethasone, irradiation and BCL-X-L. We found that the levels of MGMT expression were a major predictor of TMZ sensitivity in human glioma cells. MGMT activity and clonogenic survival after TMZ exposure are highly correlated (p < 0.0001, r(2) = 0.92). In contrast, clonogenic survival after TMZ exposure does not correlate with the expression levels of the mismatch repair proteins mutS homologue 2, mutS homologue 6 or post-meiotic segregation increased 2. The MGMT inhibitor O-6-benzylguanine sensitizes MGMT-positive glioma cells to TMZ whereas MGMT gene transfer into MGMT-negative cells confers protection. The antiapoptotic BCL-X-L protein attenuates TMZ cytotoxicity in MGMT-negative LNT-229 but not in MGMT-positive LN-18 cells. Neither ionizing radiation (4 Gy) nor clinically relevant concentrations of dexamethasone modulate MGMT activity or TMZ sensitivity. Abrogation of p53 wild-type function strongly attenuates TMZ cytotoxicity. Conversely, p53 mimetic agents designed to stabilize the wild-type conformation of p53 sensitize glioma cells for TMZ cytotoxicity. Collectively, these results suggest that the determination of MGMT expression and p53 status will help to identify glioma patients who will or will not respond to TMZ.