Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide.
Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide.
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恶性神经胶质瘤细胞端粒酶活性的抑制与其对替莫唑胺的敏感性相关。
DOI：
10.1038/sj.bjc.6601193
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发表时间：
2003-09-01
影响因子：
8.8
通讯作者：
Kondo, S
中科院分区：
文献类型：
--
作者：
Kanzawa, T;Germano, IM;Kondo, Y;Ito, H;Kyo, S;Kondo, S
替莫唑胺（TMZ，3,4-二氢-3-甲基-4-氧代咪唑[5,1-d]-四嗪-8-甲酰胺）是一种新型烷化剂，对恶性胶质瘤具有良好的抗肿瘤功效。肿瘤细胞对TMZ的耐药性主要与烷基鸟嘌呤烷基转移酶（AGT）的水平有关。 O6-苄基鸟嘌呤 (O6-BG) 是 AGT 抑制剂，可降低 TMZ 耐药性。最近，研究表明肿瘤细胞的化疗敏感性与端粒酶活性下降有关。然而，恶性胶质瘤细胞的 TMZ 敏感性是否与端粒酶相关尚不清楚。在本研究中，我们使用低水平 AGT（U373-MG 和 U87-MG）和高水平 AGT（T98G）的恶性胶质瘤细胞，研究了 AGT、端粒酶和 TMZ 敏感性之间的关联。 U373-MG和U87-MG细胞对TMZ敏感（2天治疗的IC50=100μM），而T98G细胞对TMZ耐药（2天治疗的IC50>500μM）。 TMZ (100μM) 处理以时间依赖性方式抑制 U373-MG 和 U87-MG 细胞中的端粒酶活性，但在 T98G 细胞中则不然。 U373-MG和U87-MG细胞中端粒酶活性的下调是由于转录水平上人端粒酶逆转录酶（hTERT）基因表达的抑制。这种抑制作用是通过干扰 hTERT 核心启动子的转录因子 Sp1 结合位点诱导的。有趣的是，O6-BG不仅使T98G细胞对TMZ敏感，而且还抑制端粒酶活性。这些发现表明，恶性胶质瘤细胞对 TMZ 的反应可以通过端粒酶活性的降低来监测。因此，在 TMZ 治疗期间或治疗后端粒酶活性的量化可能是检测治疗效果的有用标记。
Temozolomide (TMZ, 3,4-dihydro-3-methyl-4-oxoimidazo [5,1-d]-as-tetrazine-8-carboxamide) is a new alkylating agent with promising antitumour efficacy for malignant gliomas. The resistance of tumour cells to TMZ is primarily associated with levels of the alkylguanine alkyltransferase (AGT). O6-benzylguanine (O6-BG), an inhibitor for AGT, reduced resistance to TMZ. Recently, it has been demonstrated that chemosensitivity of tumour cells is related to a decline in telomerase activity. However, it is unknown if TMZ sensitivity of malignant glioma cells correlates with telomerase. In this study, using malignant glioma cells with low levels of AGT (U373-MG and U87-MG) and high levels of AGT (T98G), we investigated the association among AGT, telomerase, and TMZ sensitivity. U373-MG and U87-MG cells were sensitive to TMZ (IC50 for a 2-day treatment=100 μM), while T98G cells were resistant to TMZ (IC50 for a 2-day treatment >500 μM). Treatment with TMZ (100 μM) suppressed telomerase activity in U373-MG and U87-MG cells in a time-dependent manner, but not in T98G cells. The downregulation of telomerase activity in U373-MG and U87-MG cells was due to inhibition of the human telomerase reverse-transcriptase (hTERT) gene expression at the transcriptional level. This inhibitory effect was induced by interfering with transcription factor Sp1 binding sites of the hTERT core promoter. Interestingly, O6-BG not only sensitised T98G cells to TMZ, but also suppressed telomerase activity. These findings suggest that response of malignant glioma cells to TMZ can be monitored by reduction in telomerase activity. Therefore, quantification of telomerase activity during or after treatment with TMZ may be a useful marker to detect treatment efficacy.
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影响因子：
56.9
作者：
FENG, JL;FUNK, WD;VILLEPONTEAU, B
通讯作者：
VILLEPONTEAU, B
影响因子：
8
作者：
Kondo, Y;Kondo, S;Cowell, JK
通讯作者：
Cowell, JK
影响因子：
64.5
作者：
KADONAGA, JT;CARNER, KR;TIJIAN, R
通讯作者：
TIJIAN, R
影响因子：
5.1
作者：
Komata, T;Kondo, Y;Kondo, S
通讯作者：
Kondo, S
影响因子：
8.8
作者：
Baer, J C;Freeman, A A;Newlands, E S;Watson, A J;Rafferty, J A;Margison, G P
通讯作者：
Margison, G P