TUMOR ANGIOGENESIS INHIBITIION BY SYSTEMIC GENE DELIVERY

该项目的总体目标是评估血管抑制基因的全身递送作为抑制肿瘤抗生成的一种手段。具体目的是比较两种系统基因传递方法和两种血管抑制基因抑制血管生成和肿瘤生长的能力，使用实验肿瘤模型（小鼠）和假设，即通过体内基因传递持续系统产生血管抑制因子可以抑制已建立肿瘤的动物的血管生成。这一建议的基本原理是，通过系统的非病毒基因传递技术在体内持续表达血管抑制基因，可能是比反复注射纯化蛋白更有效和实用的血管生成抑制方法。两种内源性血管抑制素（内皮抑素和血管抑素）在体内均表现出令人印象深刻的抗肿瘤活性，将进行评估。本提案的目标将通过三个具体目标来实现：(1)比较小鼠肿瘤模型中静脉注射和肌肉注射基因传递的有效性；(2)确定犬静脉注射和肌肉注射基因的最佳DNA剂量；(3)评估犬恶性黑色素瘤系统性内皮抑素基因治疗的抗血管生成活性和肿瘤反应。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，将为这种抑制肿瘤血管生成的新方法提供临床现实的评估。这种方法可能广泛适用于血管生成的治疗性调节，通常使用抑制或刺激血管生成的基因或基因组合。

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.