Biglari Alireza, Bataille Dominique, Naumann Ulrike, Weller Michael, Zirger Jeffrey, Castro Maria G, Lowenstein Pedro R
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Research Pavilion, Suite 5090, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
Cancer Gene Ther. 2004 Nov;11(11):721-32. doi: 10.1038/sj.cgt.7700783.
Given the failure of conventional treatments for glioblastoma, gene therapy has gained interest considerable in recent years. Gliomas are associated with a state of immunosuppression, which appears to be partially mediated by an increase in secretion of transforming growth factor-beta (TGF-beta) from glioma cells. Decorin, a small proteoglycan which can bind to and inactivate TGF-beta, has been successfully used as an antitumor strategy on stably transfected tumor cells and has been shown to cause growth suppression in neoplastic cells of various histological origins. In this paper, we investigated the use of gene therapy to deliver the decorin transgene in a site-specific manner in an experimental model of intracranial gliomas. Our aim was to inhibit the glioma-associated immunosuppressive state, and prolong the survival of tumor-bearing rats. We studied the effects of decorin gene transfer in the rat CNS-1 glioma model. To assess the effect of ectopic expression of decorin on glioma progression in vivo, stably transfected CNS-1 cells expressing decorin were implanted into the brain parenchyma of syngeneic Lewis rats. The rats implanted with CNS-1 cells expressing decorin survived significantly longer than those in the control groups which received CNS-1 cells that did not express decorin (P < .0001). We then investigated whether the survival observed with decorin expressing cells could be mimicked in vivo, using recombinant adenoviruses (RAds) expressing the decorin gene under the control of two different promoters: the human immediate-early cytomegalovirus (h-IE-CMV) and the glial fibrillary acidic protein (GFAP). In vivo results showed that administration of RAd expressing the human decorin under the control of h-IE-CMV promoter has a small, but significant effect in prolonging the survival of experimental tumor bearing rats (P < .0001). Our data indicate that ectopic decorin expression has the potential to slow glioma progression in vivo. Our results also indicate that expression of decorin has to be present in all cells which constitute the intracranial tumor mass for the inhibition of tumor growth and prolongation of the life expectancy of tumor-bearing rats to be effective.
鉴于胶质母细胞瘤的传统治疗方法效果不佳，近年来基因治疗受到了广泛关注。胶质瘤与免疫抑制状态相关，这种状态似乎部分是由胶质瘤细胞中转化生长因子-β（TGF-β）分泌增加介导的。核心蛋白聚糖是一种能结合并使TGF-β失活的小蛋白聚糖，已成功用于稳定转染的肿瘤细胞的抗肿瘤策略，并已显示出对各种组织学来源的肿瘤细胞具有生长抑制作用。在本文中，我们研究了在颅内胶质瘤实验模型中以位点特异性方式递送核心蛋白聚糖转基因的基因治疗方法。我们的目的是抑制胶质瘤相关的免疫抑制状态，并延长荷瘤大鼠的生存期。我们研究了核心蛋白聚糖基因转移在大鼠CNS-1胶质瘤模型中的作用。为了评估核心蛋白聚糖异位表达对体内胶质瘤进展的影响，将稳定转染表达核心蛋白聚糖的CNS-1细胞植入同基因Lewis大鼠的脑实质中。植入表达核心蛋白聚糖的CNS-1细胞的大鼠存活时间明显长于接受未表达核心蛋白聚糖的CNS-1细胞的对照组（P <.0001）。然后，我们研究了使用在两种不同启动子控制下表达核心蛋白聚糖基因的重组腺病毒（RAds），是否能在体内模拟表达核心蛋白聚糖的细胞所观察到的生存期延长情况。这两种启动子分别是人立即早期巨细胞病毒（h-IE-CMV）和胶质纤维酸性蛋白（GFAP）。体内结果表明，在h-IE-CMV启动子控制下给予表达人核心蛋白聚糖的RAd对延长实验性荷瘤大鼠的生存期有微小但显著的作用（P <.0001）。我们的数据表明，异位核心蛋白聚糖表达有可能在体内减缓胶质瘤的进展。我们的结果还表明，核心蛋白聚糖的表达必须存在于构成颅内肿瘤块的所有细胞中，才能有效抑制肿瘤生长并延长荷瘤大鼠的预期寿命。
