胸苷激酶
胶质瘤
生物
癌症研究
遗传增强
细胞凋亡
程序性细胞死亡
联合疗法
自杀基因
激活剂(遗传学)
半胱氨酸蛋白酶
细胞毒性T细胞
单纯疱疹病毒
病毒学
体外
病毒
基因
药理学
遗传学
作者
Takashi Yamaguchi,Takashi Okada,Koichi Takeuchi,Tetsuji Tonda,Megu Ohtaki,Souji Shinoda,Toshio Masuzawa,Keiya Ozawa,Toshiya Inaba
出处
期刊:Gene Therapy
[Springer Nature]
日期:2003-02-25
卷期号:10 (5): 375-385
被引量:22
标识
DOI:10.1038/sj.gt.3301897
摘要
Herpes simplex virus thymidine kinase (HSV-tk)/gancyclovir (GCV) therapy has the ability to inhibit tumor formation in animal models but the results of clinical trials have been disappointing. To improve the performance of tk/GCV therapy, we tried combination therapy designed to enhance its cytotoxic effects by introducing genes that induce apoptosis of the tumor cells through different pathways. We concentrated our efforts on the use of Bim, a BH3-only member of death activators in the Bcl-2 superfamily, because Bim is not involved in the pathways through which HSV-tk/GCV therapy induces apoptosis in malignant glioma cells. Among three alternative splicing variants, BimEL, BimL, and BimS, BimS lacks the binding domain for the dynein light chain LC8, which negatively regulates the proapoptotic function of BimEL and BimL. All four malignant glioma cell lines, U251, A172, T-430, and U373 underwent cell death after transfer of BimS using an adenovirus vector (AVC2). Intriguingly, combination of AVC2-BimS with AVC2-tk markedly increased the sensitivity of U251 cells to GCV both in vitro and in vivo. In contrast, AVC2-BimL did not induce significant cell death. These results indicated that BimS had the ability to improve the efficiency of HSV-tk/GCV therapy in the treatment of malignant glioma and suggested that the targeting of different proapoptotic pathways may be a useful strategy for the development of an effective gene therapy approach to treatment.
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