O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines
O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines
复制标题
DOI：
10.1158/1078-0432.ccr-04-2045
复制
发表时间：
2005-04-01
影响因子：
11.5
通讯作者：
Goff, RD
中科院分区：
文献类型：
--
作者：
Bobola, MS;Silber, JR;Goff, RD
目的：原发性脑肿瘤是儿童癌症死亡的主要原因。我们的目的是(A)评估DNA修复蛋白O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)在儿童脑瘤细胞系对临床烷化药物耐药中的作用，以及(B)评估MGMT抑制剂O-6-苄基鸟嘌呤最大限度增强细胞杀伤作用的变量，目前正在进行临床试验。目前很少有关于儿童胶质瘤系的此类数据，特别是那些来自低级别肿瘤的数据。实验设计：我们使用克隆性增殖存活试验来定量氯乙基化试剂1，3-二(2-氯乙基)-1-亚硝脲(BCNU)和甲基化试剂替莫唑胺在11个胶质瘤和5个髓母细胞瘤系中的细胞毒性。这里新建立了12个细胞系，其中9个来自包括毛细胞性星形细胞瘤在内的低级别胶质瘤。结果：(A)在我们的胶质瘤和髓母细胞瘤中，MGMT是BCNU耐药的主要决定因素，也是替莫唑胺耐药的主要决定因素。在15个MGMT表达系中，O-6-苄基鸟嘌呤使BCNU和替莫唑胺的LD10分别降低了2.6倍和26倍。(B)O-6-苄基鸟嘌呤使BCNU和替莫唑胺的杀伤阈值剂量分别降低了3.3倍和138倍。D-T从高于或低于两种烷化剂的临床可达到的血浆剂量的水平降低。(C)O-6-苄基鸟嘌呤的最大增强作用需要完全和长时间地抑制MGMT。结论：我们的结果支持在儿童脑肿瘤的化疗中使用O-6-苄基鸟嘌呤以充分发挥烷化剂，特别是替莫唑胺的益处。
Purpose: Primary brain tumors are the leading cause of cancer death in children. Our purpose is (a) to assess the contribution of the DNA repair protein O-6-methylguanine-DNA methyltransferase (MGMT) to the resistance of pediatric brain tumor cell lines to clinical alkylating agents and (b) to evaluate variables for maximal potentiation of cell killing by the MGMT inhibitor O-6-benzylguanine, currently in clinical trials. Few such data for pediatric glioma lines, particularly those from low-grade tumors, are currently available.Experimental design: We used clonogenic assays of proliferative survival to quantitate cytoxicity of the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the methylating agent temozolomide in 11 glioma and five medulloblastoma lines. Twelve lines are newly established and characterized here, nine of them from low-grade gliomas including pilocytic astrocytomas. Results: (a) MGMT is a major determinant of BCNU resistance and the predominant determinant of temozolomide resistance in both our glioma and medulloblastoma lines. On average, O-6-benzylguanine reduced LD10 for BCNU and temozolomide, 2.6- and 26-fold, respectively, in 15 MGMT-expressing lines. (b) O-6-Benzylguanine reduced D-T (the threshold dose for killing) for BCNU and temozolomide, 3.3- and 138-fold, respectively. D-T was decreased from levels higher than, to levels below, clinically achievable plasma doses for both alkylators. (c) Maximal potentiation by O-6-benzylguanine required complete and prolonged suppression of MGMT.Conclusions: Our results support the use of O-6-benzylguanine to achieve full benefit of alkylating agents, particularly temozolomide, in the chemotherapy of pediatric brain tumors.