Nilaver G, Muldoon L L, Kroll R A, Pagel M A, Breakefield X O, Davidson B L, Neuwelt E A
Department of Neurology, Oregon Health Sciences University, Portland 97201, USA.
Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9829-33. doi: 10.1073/pnas.92.21.9829.
The delivery of viral vectors to the brain for treatment of intracerebral tumors is most commonly accomplished by stereotaxic inoculation directly into the tumor. However, the small volume of distribution by inoculation may limit the efficacy of viral therapy of large or disseminated tumors. We have investigated mechanisms to increase vector delivery to intracerebral xenografts of human LX-1 small-cell lung carcinoma tumors in the nude rat. The distribution of Escherichia coli lacZ transgene expression from primary viral infection was assessed after delivery of recombinant virus by intratumor inoculation or intracarotid infusion with or without osmotic disruption of the blood-brain barrier (BBB). These studies used replication-compromised herpes simplex virus type 1 (HSV; vector RH105) and replication-defective adenovirus (AdRSVlacZ), which represent two of the most commonly proposed viral vectors for tumor therapy. Transvascular delivery of both viruses to intracerebral tumor was demonstrated when administered intraarterially (i.a.) after osmotic BBB disruption (n = 9 for adenovirus; n = 7 for HSV), while no virus infection was apparent after i.a. administration without BBB modification (n = 8 for adenovirus; n = 4 for HSV). The thymidine kinase-negative HSV vector infected clumps of tumor cells as a result of its ability to replicate selectively in dividing cells. Osmotic BBB disruption in combination with i.a. administration of viral vectors may offer a method of global delivery to treat disseminated brain tumors.
将病毒载体递送至脑部以治疗脑内肿瘤，最常用的方法是通过立体定向接种直接注入肿瘤。然而，接种后的分布体积较小可能会限制对大肿瘤或播散性肿瘤的病毒治疗效果。我们研究了增加病毒载体递送至裸鼠体内人LX-1小细胞肺癌脑内异种移植物的机制。在通过瘤内接种或颈内动脉注射重组病毒（伴或不伴有血脑屏障（BBB）的渗透性破坏）后，评估原发性病毒感染产生的大肠杆菌β-半乳糖苷酶转基因表达的分布。这些研究使用了复制受损的1型单纯疱疹病毒（HSV；载体RH105）和复制缺陷型腺病毒（AdRSVlacZ），它们是最常被提议用于肿瘤治疗的两种病毒载体。当在渗透性血脑屏障破坏后经动脉内（i.a.）给药时，两种病毒均显示可经血管递送至脑内肿瘤（腺病毒n = 9；HSV n = 7），而在未经血脑屏障修饰的动脉内给药后未观察到明显的病毒感染（腺病毒n = 8；HSV n = 4）。胸苷激酶阴性的HSV载体由于其在分裂细胞中选择性复制的能力而感染肿瘤细胞团块。渗透性血脑屏障破坏与病毒载体的动脉内给药相结合，可能提供一种用于治疗播散性脑肿瘤的整体递送方法。
