Effective treatment of experimental glioblastoma by HSV vector-mediated TNFα and HSV-tk gene transfer in combination with radiosurgery and ganciclovir administration
Effective treatment of experimental glioblastoma by HSV vector-mediated TNFα and HSV-tk gene transfer in combination with radiosurgery and ganciclovir administration
复制标题
DOI：
10.1006/mthe.2000.0101
复制
发表时间：
2000-08-01
影响因子：
12.4
通讯作者：
Glorioso, JC
中科院分区：
文献类型：
--
作者：
Niranjan, A;Moriuchi, S;Glorioso, JC
在人胶质母细胞瘤裸鼠模型中进行了实验，以确定伽玛刀放射外科手术联合单纯疱疹病毒胸苷激酶（tk）自杀基因治疗和肿瘤坏死因子α（TNFα）基因转移是否为该疾病提供了改进的多模式治疗。动物脑内接种 2 X 10(5) U-87MG 人胶质母细胞瘤细胞以建立脑肿瘤。接种后 3 天，向肿瘤区域注射 2 x 10(6) 个高度缺陷型单纯疱疹病毒载体感染性颗粒，表达病毒 tk 基因，具有病毒立即早期基因的动力学，无论是单独的 (T.1) 还是与 TNF α (TH:TNF) 一起。对动物亚组进行为期 10 天的更昔洛韦 (GCV) 乳制品腹腔注射和/或在肿瘤细胞植入后第五天进行伽马刀放射外科治疗。动物存活率比较表明，TH:TNF 载体结合放射外科和 GCV 给药提供了最有效的治疗；九只动物中有八只存活了 75 天，而使用次佳方案的八只动物中有四只存活了 75 天。这些发现表明，基因疗法与更传统的治疗方法相结合可能会提供一种改进的策略，以延长患有这种最终致命疾病的患者的预期寿命。
Experiments were carried out in a nude mouse model of human glioblastoma to determine whether gamma-knife radiosurgery combined with herpes simplex virus thymidine kinase (tk) suicide gene therapy and tumor necrosis factor alpha (TNF alpha) gene transfer provided an improved multimodality treatment of this disease. Animals were inoculated intracerebrally with 2 X 10(5) U-87MG human glioblastoma cells to establish brain tumors. At 3 days postinoculation, the tumor region was injected with 2 x 10(6) infectious particles of highly defective herpes simplex viral vectors expressing the viral tk gene with the kinetics of a viral immediate early gene either alone (T.1) or together with TNF alpha (TH:TNF). Subgroups of animals were given dairy intraperitoneal injections of ganciclovir (GCV) for 10 days and/or subjected to gamma-knife radiosurgery on the fifth day post tumor-cell implantation. Comparisons of animal survival showed that the TH:TNF vector in combination with radiosurgery and GCV administration provided the most effective therapy; eight of nine animals survived for 75 days compared to four of eight using the next best protocol. These findings suggest that gene therapy in combination with more conventional therapeutic methods may provide an improved strategy for extending the life expectancy of patients afflicted with this ultimately fatal disease.