SOFT TISSUE SARCOMA--P53 AND VEGF INDUCTION

描述：（申请人的摘要）软组织肉瘤是一种毁灭性的 涉及假定的间充质细胞起源的肿瘤的恶性肿瘤。软 组织肉瘤五年总生存率一直停滞在50%左右 在过去的三十年里。没有新的治疗方法被引入 自从多柔比星多药化疗方案在 70年代初软组织中最常见的基因突变 肉瘤是p53肿瘤抑制基因的改变，发生在30-60 所有这些肿瘤的百分比。肉瘤处活跃的新生血管形成：正常 组织界面是宏观可观察的， 危及手术切除性。大的中央缺氧肿瘤核心 当这些恶性肿瘤增殖并超过其血液时， 供应对肿瘤血管生成的新认识促使了许多 有兴趣利用这一组成部分的恶性表型作为一个潜在的 治疗靶点虽然对软组织中的血管生成知之甚少， p53突变、肿瘤缺氧导致的恶性肿瘤 一氧化氮诱导，血管内皮生长因子（VEGF） 促使申请人考虑以下具体目标：1）调查 p53基因突变对STS中VEGF诱导的病理生物学影响。（二） 研究STS中p53基因调控VEGF的分子机制。 3)开发抑制STS的实验性分子治疗方法 通过靶向突变的p53基因和VEGF表达来治疗进展。解决这些 为了达到特定的目的，将采用一种实验设计， 对p53的生物学和机制进行深入的分子基础研究 VEGF的诱导，以及一氧化氮在这一过程中的作用。 临床前治疗干预也将考虑利用 野生型p53基因恢复疗法联合抗VEGF方法 （反义VEGF和抗VEGF受体单克隆抗体治疗）。 隔离肢体灌注已经被接受为标准的输送手段 大剂量化疗治疗肢体肉瘤裸鼠人肉瘤异种移植瘤 已经在申请人的实验室建立的模型将被用作一种新的 将上述治疗性构建体直接递送到人体内的方法 肉瘤异种移植物希望通过成功完成这一项目， 申请人将加强我们对以下监管相互作用的了解： p53和VEGF在软组织肉瘤中的作用，导致随后的临床试验， 人类将解决这些分子紊乱，也许通过新的 离体肢体灌注基因传递系统。

DESCRIPTION: (Applicant's Abstract) Soft tissue sarcoma is a devastating malignancy involving tumors of putative mesenchymal cell origin. The soft tissue sarcoma five year overall survival rate of 50 percent has been stagnant for the past thirty years. No fundamentally new therapies have been introduced since the inception of doxorubicin multi-drug chemotherapy regimens in the early 1970s. The most frequently encountered genetic mutation in soft tissue sarcoma is alteration in the p53 tumor suppressor gene, which occurs in 30-60 percent of all such tumors. Brisk neovascularization at the sarcoma:normal tissue interface is macroscopically observable and occasionally can even compromise surgical resectability. Large central cores of hypoxic tumor necrosis are seen as these malignancies proliferate and outstrip their blood supply. An emerging awareness about tumor angiogenesis has prompted much interest in exploiting this component of the malignant phenotype as a potential therapeutic target. While little is known about angiogenesis in soft tissue sarcoma, the interrelationship between p53 mutation, tumor hypoxia leading to nitric oxide induction, and vascular endothelial growth factor (VEGF) has prompted the applicant to consider the following specific aims: 1) Investigate the pathobiologic impact of p53 gene mutation on VEGF induction in STS. 2) Examine the molecular mechanisms underlying p53 gene regulation of VEGF in STS. 3) Develop experimental molecular therapeutic approaches that inhibit STS progression by targeting mutated p53 gene and VEGF expression. To address these specific aims, an experimental design will be utilized that incorporates an in depth molecular based examination of the biology and mechanisms underlying p53 induction of VEGF, as well as the role of nitric oxide in this process. Preclinical therapeutic interventions will also be considered utilizing wild-type p53 gene restoration therapy combined with anti-VEGF approaches (antisense VEGF and anti-VEGF receptor monoclonal antibody treatments). Isolated limb perfusion is already accepted as a standard means of delivering high dose chemotherapy to extremity sarcoma. A nude rat human sarcoma xenograft model already established in the applicant's laboratory will be used as a novel means of delivering the above therapeutic constructs directly into human sarcoma xenografts. It is hoped that by successfully completing this project the applicant will enhance our knowledge of the regulatory interaction between p53 and VEGF in soft tissue sarcoma, leading to subsequent clinical trials in humans that will address these molecular derangements, perhaps via novel isolated limb perfusion gene delivery systems.