Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice
Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice
复制标题
DOI：
10.1002/ijc.22278
复制
发表时间：
2007-01-15
影响因子：
6.4
通讯作者：
Vallera, Daniel A.
中科院分区：
文献类型：
--
作者：
Rustamzadeh, Edward;Hall, Walter A.;Vallera, Daniel A.
采用基因拼接技术构建了一种融合蛋白DTAT，该融合蛋白编码白喉毒素（DT 390）的390个氨基酸部分、一个接头和人尿激酶纤溶酶原激活剂的下游135-氨基末端片段部分。在小鼠颅内模型中组装DTAT以靶向人胶质母细胞瘤细胞系。以前发表的体外研究表明，DTAT是高度选择性和毒性的人胶质母细胞瘤细胞系在侧腹肿瘤模型。本研究的目的是确定DTAT在颅内模型中的毒性、特异性和可能的治疗效果。DTAT的对流增强递送导致最大耐受剂量增加约16倍。在已建立U87 MG脑肿瘤的裸鼠中，每隔一天颅内给予DTAT导致肿瘤体积显著减小，存活期显著延长（p < 0.0001）。在小鼠和大鼠中，磁共振成像被证明是一种强有力的工具，可用于证明异种移植颅内模型中的肿瘤生长，评估DTAT在肿瘤体积缩小中的疗效，并检测DTAT相关的颅内毒性和血管损伤。这些结果表明，DTAT重组融合蛋白在颅内模型中是高度有效的，并且DTAT可能是胶质母细胞瘤的有效治疗。(c)2006威利-利斯公司
A gene splicing technique was used to create a hybrid fusion protein DTAT encoding the 390 amino acid portion of diphtheria toxin (DT390), a linker, and the downstream 135-amino terminal fragment portion of human urokinase plasminogen activator. DTAT was assembled to target human glioblastoma cell lines in a murine intracranial model. Previously published in vitro studies demonstrated that DTAT was highly selective and toxic to human glioblastoma cell lines in a flank tumor model. The purpose of this study was to determine the toxicity, specificity and possible therapeutic efficacy of DTAT in an intracranial model. Convection enhanced delivery of DTAT resulted in about a 16-fold increase in maximum tolerated dose. Intracranial administration of DTAT on an every-other-day basis in nude mice with established U87 MG brain tumors resulted in significant reductions in tumor volume and significantly prolonged survival (p < 0.0001). Magnetic resonance imaging proved to be a powerful tool in mice and rats for demonstrating tumor growth in a xenograft intracranial model, assessing the efficacy of DTAT in tumor volume reduction and detecting DTAT-associated intracranial toxicity and vascular damage. These results suggest that the DTAT recombinant fusion protein is highly effective in an intracranial model and DTAT might be an effective treatment for glioblastoma. (c) 2006 Wiley-Liss, Inc.