Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids.
Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids.
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DOI：
10.1038/sj.bjc.6600711
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发表时间：
2003-02-10
影响因子：
8.8
通讯作者：
Terzis, AJ
中科院分区：
文献类型：
--
作者：
Günther, W;Pawlak, E;Damasceno, R;Arnold, H;Terzis, AJ
替莫唑胺是一种烷基化细胞抑制剂，在黑色素瘤、间变性星形细胞瘤和多形性胶质母细胞瘤的治疗中得到越来越多的应用。该化合物是一种不依赖于酶活化步骤而自发分解的前药。DNA甲基化导致无效的错配修复循环，DNA修复酶O6-甲基鸟嘌呤-DNA甲基转移酶的耗尽应启动细胞程序性死亡。我们在胶质瘤细胞系U87 MG和GAMG的三维细胞培养模型中显示了药物对肿瘤生长的抑制作用。胶质母细胞瘤细胞的迁移行为没有改变。然而，在替莫唑胺存在的情况下，肿瘤球体与初级脑聚集体共孵育显示，肿瘤细胞对脑组织的侵袭减少。这不是通过减缓细胞迁移来实现的，因为替莫唑胺处理的细胞没有表现出运动性降低。通过转移酶介导的dUTP缺口末端标记法(TUNEL)，我们发现该药物能够诱导整个肿瘤细胞球体的凋亡。球体核心区细胞凋亡率最高。重复亚致死剂量替莫唑胺作用于多细胞球体可导致GAMG细胞产生耐药性。我们认为替莫唑胺是球形细胞培养系统中胶质母细胞瘤肿瘤细胞凋亡的有力启动者，而细胞已经处于应激环境中。
Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O6-methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a three-dimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment.
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影响因子：
3
作者：
TSANG, LLH;QUARTERMAN, CP;SLACK, JA
通讯作者：
SLACK, JA
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
12.4
作者：
Tentori, L;Portarena, I;Graziani, G
通讯作者：
Graziani, G
影响因子：
2.3
作者：
Sankar, A;Thomas, DGT;Darling, JL
通讯作者：
Darling, JL
影响因子：
8.8
作者：
Terzis AJ;Thorsen F;Heese O;Visted T;Bjerkvig R;Dahl O;Arnold H;Gundersen G
通讯作者：
Gundersen G