Van Houdt Winan J, Haviv Yosef S, Lu Baogen, Wang Minghui, Rivera Angel A, Ulasov Ilya V, Lamfers Martine L M, Rein Daniel, Lesniak Maciej S, Siegal Gene P, Dirven Clemens M F, Curiel David T, Zhu Zeng B
Department of Neurosurgery, VU Universiteit Medische Center, Amsterdam, The Netherlands.
J Neurosurg. 2006 Apr;104(4):583-92. doi: 10.3171/jns.2006.104.4.583.
Malignant brain tumors have been proved to be resistant to standard treatments and therefore require new therapeutic strategies. Survivin, a recently described member of the inhibitor of apoptosis protein family, is overexpressed in several human brain tumors, primarily gliomas, but is downregulated in normal tissues. The authors hypothesized that the expression of tumor-specific survivin could be exploited for treatment of gliomas by targeting the tumors with gene therapy vectors.
Following confirmation of survivin expression in glioma cell lines, an adenoviral vector containing the survivin promoter and the reporter gene luciferase was tested in established and primary glioma cells, normal astrocytic cells, and normal human brain tissues. High levels of reporter gene expression were observed in established tumor and primary tumor cell lines and low levels of expression in astrocytes and normal human brain tissue. To test oncolytic potency, the authors constructed survivin promoter-based conditionally replicative adenoviruses (CRAds), composed of survivin promoter-regulated E1 gene expression and an RGD-4C capsid modification. These CRAds could efficiently replicate within and kill a variety of established glioma tumor cells, but were inactive in a normal human liver organ culture. Finally, survivin promoter-based CRAds significantly inhibited the growth of glioma xenografts in vivo.
Together these data indicate that the survivin promoter is a promising tumor-specific promoter for transcriptional targeting of adenovirus-based vectors and CRAds for malignant gliomas. The strategy of using survivin-CRAds may thus translate into an experimental therapeutic approach that can be used in human clinical trials.
恶性脑肿瘤已被证明对标准治疗具有抗性，因此需要新的治疗策略。Survivin是凋亡抑制蛋白家族中最近被描述的成员，在几种人类脑肿瘤中过度表达，主要是神经胶质瘤，但在正常组织中表达下调。作者推测，通过用基因治疗载体靶向肿瘤，可以利用肿瘤特异性Survivin的表达来治疗神经胶质瘤。
在确认神经胶质瘤细胞系中Survivin表达后，在已建立的和原发性神经胶质瘤细胞、正常星形胶质细胞和正常人类脑组织中测试了一种含有Survivin启动子和报告基因荧光素酶的腺病毒载体。在已建立的肿瘤和原发性肿瘤细胞系中观察到高水平的报告基因表达，而在星形胶质细胞和正常人类脑组织中表达水平较低。为了测试溶瘤效力，作者构建了基于Survivin启动子的条件性复制腺病毒（CRAds），其由Survivin启动子调节的E1基因表达和RGD-4C衣壳修饰组成。这些CRAds可以在多种已建立的神经胶质瘤肿瘤细胞内有效复制并杀死它们，但在正常人类肝脏器官培养中无活性。最后，基于Survivin启动子的CRAds在体内显著抑制了神经胶质瘤异种移植瘤的生长。
这些数据共同表明，Survivin启动子是一种有前景的肿瘤特异性启动子，可用于基于腺病毒的载体和CRAds对恶性神经胶质瘤进行转录靶向。因此，使用Survivin-CRAds的策略可能转化为一种可用于人类临床试验的实验性治疗方法。
