TUMOR ANGIOGENESIS INHIBITIION BY SYSTEMIC GENE DELIVERY

该项目的总体目标是评估血管生成抑制基因的全身递送作为抑制肿瘤抗原生成的手段。 具体的目标是比较两种方法的全身基因传递和两种血管生成抑制基因的能力，以抑制血管生成和肿瘤生长，使用实验肿瘤模型（小鼠）和假设，持续全身生产的血管生成抑制因子的体内基因传递可以抑制血管生成的动物与建立的肿瘤。 该提议的基本原理是，通过系统性非病毒基因递送技术持续体内表达血管生成抑制基因可能是比重复胃肠外注射纯化蛋白质更有效和实用的血管生成抑制方法。 两个内源性血管生成抑制因子（内皮抑素和血管抑素），这两个都表现出令人印象深刻的体内抗肿瘤活性，将进行评估。本提案的目的将通过三个具体目标实现：（1）比较静脉内与肌肉内基因递送在鼠肿瘤模型中的有效性;（2）确定犬静脉内和肌肉内基因递送的最佳DNA剂量;（3）评估恶性黑色素瘤犬的抗血管生成活性和对全身性内皮抑制素基因治疗的肿瘤反应。 这些研究的结果，包括在相关的大型动物肿瘤模型中评估血管生成标志物和治疗结果，将提供对这种抑制肿瘤血管生成的新方法的临床现实评价。 这样的方法可以广泛地适用于使用抑制或刺激血管生成的基因或基因组合来治疗性调节一般的血管生成。

The overall goal of this project is to assess systemic delivery of angiostatic genes as a means of inhibiting tumor antiogenesis. The specific objectives are to compare two methods of systemic gene delivery and two angiostatic genes for their ability to inhibit angiogenesis and tumor growth, using both experimental tumor models (mice) and hypothesis that sustained systemic production of an angiostatic factor by in vivo gene delivery can inhibit angiogenesis in animals with established tumors. The rationale for this proposal is that sustained in vivo expression of angiostatic genes by systemic non-viral gene delivery techniques may be a more effective and practical approach to angiogenesis inhibition than repeated parenteral injections of purified proteins. Two endogenous angiostatic factors (endostatin and angiostatin), that have both demonstrated impressive antitumor activity in vivo, will be evaluated. The objective of this proposal will be accomplished using three specific aims: (1) compare the effectiveness of intravenous versus intramuscular gene delivery in murine tumor models; (2) determine optimal DNA doses for intravenous and intramuscular gene delivery in dogs; and (3) assess antiangiogenic activity and tumor responses to systemic endostatin gene therapy in dogs with malignant melanoma. The results of these studies, which include assessment of angiogenic markers and treatment outcomes in a pertinent large animal tumor model, will provide a clinically realistic evaluation of this novel approach to inhibition to tumor angiogenesis. Such an approach may be broadly applicable to therapeutic modulation of aniogenesis in general, using genes or combinations of genes that either inhibit or stimulate angiogenesis.