新药替莫唑胺酯抗原发性耐药胶质瘤机制研究

丁凤霞; 郭珊珊; 阎昭<sup>*</sup>

引用本文:	丁凤霞,郭珊珊,阎昭.新药替莫唑胺酯抗原发性耐药胶质瘤机制研究[J].中国现代应用药学,2016,33(1):27-32.
	DING Fengxia,GUO Shanshan,YAN Zhao.Mechanism of New Drug Temozolomide Easter on Primary Resistance Glioma[J].Chin J Mod Appl Pharm(中国现代应用药学),2016,33(1):27-32.

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新药替莫唑胺酯抗原发性耐药胶质瘤机制研究
丁凤霞, 郭珊珊, 阎昭
天津医科大学肿瘤医院临床药理室，国家肿瘤临床医学研究中心，天津市肿瘤防治重点实验室，天津 300060

摘要:

目的以替莫唑胺(temozolomide，TMZ)为阳性对照，研究新药替莫唑胺酯(temozolomide hexyl ester，TMZ-HE)在体外抑制脑胶质瘤T98G细胞生长并诱导凋亡的作用及其机制。方法 MTT比色法和克隆形成实验比较TMZ和TMZ-HE对细胞增殖的影响；流式细胞仪检测TMZ-HE和TMZ对细胞凋亡率及细胞周期的影响；Western blot检测TMZ和TMZ-HE对Bax、Bcl-2以及O⁶-甲基鸟嘌呤-DNA甲基转移酶(O⁶-methyl-oguanine-DNA-methyltransferase，MGMT)、γH2AX蛋白表达的影响。结果 TMZ-HE较TMZ明显抑制T98G细胞的生长，呈浓度及时间依赖性，长期作用时效果更加明显；TMZ-HE诱导T98G细胞凋亡率高于TMZ；TMZ-HE能够导致T98G细胞发生G2期阻滞；TMZ-HE能够增加Bax/Bcl-2的比值，诱导发生凋亡，TMZ-HE比TMZ更明显地消耗MGMT，产生更强的DNA损伤。结论 TMZ-HE对胶质瘤T98G细胞的增殖抑制及诱导凋亡的作用优于TMZ，消耗MGMT以及DNA损伤能力强于TMZ。

关键词: 替莫唑胺酯多形性脑胶质瘤细胞凋亡耐药

DOI：

分类号:

基金项目:十二五“重大新药创制”科技重大专项课题(2013ZX09303001)

Mechanism of New Drug Temozolomide Easter on Primary Resistance Glioma

DING Fengxia, GUO Shanshan, YAN Zhao

Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China

Abstract:

OBJECTIVE To investigate the effect of temozolomide(TMZ) hexyl easter(TMZ-HE) on the proliferation and apoptosis of brain glioma T98G cells in vitro compared with TMZ, and then illustrate the mechanism. METHODS Methyl thiazolyl tetrazolium (MTT) assay and colony formation assay was used to compare the effect of TMZ and TMZ-HE on cell proliferation. Cell apoptosis rate and cell cycle induced by TMZ and TMZ-HE were analyzed by flow cytometry. Western blot was used to detect the expression of Bax, Bcl-2, O⁶-methyl-oguanine-DNA-methyltransferase(MGMT), γH2AX after treated with TMZ and TMZ-HE. RESULTS TMZ-HE obviously suppressed the cell proliferation in a concentration and time-dependent manner compared with TMZ, and it was more obvious in long-term effect; TMZ-HE induced more cellular apoptosis of the T98G cells than TMZ; TMZ-HE induced a distinct G2 arrest in T98G cell; TMZ-HE induced apoptosis by increasing the ratio of Bax/Bcl-2, TMZ-HE consumed MGMT more significant than TMZ, and produced more DNA damage. CONCLUSION TMZ-HE has an advantage over the effect of anti-proliferative and induced apoptosis than TMZ, and the ability of TMZ-HE to consume MGMT and DNA damage is improved.

Key words: temozolomide hexyl ester glioblastoma multiforme cell apoptosis resistance