Benítez J A, Arregui L, Vergara P, Segovia J
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México DF, México.
Cancer Gene Ther. 2007 Oct;14(10):836-46. doi: 10.1038/sj.cgt.7701076. Epub 2007 Jun 29.
The targeted expression of transgenes is one of the principal goals of gene therapy, and it is particularly relevant for the treatment of brain tumors. In this study, we examined the effect of the overexpression of human gas1 (growth arrest specific 1) and human p53 cDNAs, both under the transcriptional control of a promoter of the human glial fibrillary acidic protein (gfa2), employing adenoviral expression vectors, in glioma cells. We showed that the targeted overexpression of gas1 and p53 (AdSGas1 and AdSp53, respectively) in rat glioma cells (C6) reduced the number of viable cells and induced apoptosis. Moreover, the adenovirally targeted expression of these genes also reduced tumor growth in vivo. Unexpectedly, there was no additive effect when both gas1 and p53 were simultaneously expressed in the same cells using a bicistronic adenoviral vector. We suggest that Gas1 does not act in combination with p53 in the C6 and U373 glioma cell lines, inducing apoptosis and cell cycle arrest. Our results indicate that the targeted expression of tumor suppressor genes (gas1 and p53) regulated by the gfa2 promoter, together with adenoviral vectors may provide an interesting approach for adjuvant selective glioma gene therapy.
转基因的靶向表达是基因治疗的主要目标之一，尤其与脑肿瘤的治疗相关。在本研究中，我们使用腺病毒表达载体，检测了在人胶质纤维酸性蛋白（gfa2）启动子的转录控制下，人gas1（生长停滞特异性蛋白1）和人p53 cDNA过表达对胶质瘤细胞的影响。我们发现，在大鼠胶质瘤细胞（C6）中gas1和p53的靶向过表达（分别为AdSGas1和AdSp53）减少了活细胞数量并诱导了凋亡。此外，这些基因的腺病毒靶向表达在体内也减少了肿瘤生长。出乎意料的是，当使用双顺反子腺病毒载体在同一细胞中同时表达gas1和p53时，没有相加效应。我们认为，在C6和U373胶质瘤细胞系中，Gas1不与p53协同作用来诱导凋亡和细胞周期停滞。我们的结果表明，由gfa2启动子调控的肿瘤抑制基因（gas1和p53）与腺病毒载体的靶向表达可能为辅助性选择性胶质瘤基因治疗提供一种有趣的方法。
