Generation of Antiangiogenic Activity for Cancer Treat.

产生用于癌症治疗的抗血管生成活性。

• 批准号: 6748971
• 负责人: VIKAS P SUKHATME
• 金额: $ 31.93万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748971
• 关键词: angiogenesis inhibitors; antineoplastics; breast neoplasms; captopril; cell proliferation; cell surface receptors; chromatography; clinical research; clinical trial phase I; combination chemotherapy; disease /disorder model; drug screening /evaluation; enzyme linked immunosorbent assay; fibroblast growth factor; gene therapy; human subject; human therapy evaluation; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic process; patient oriented research; plasminogen activator; thrombin; transfection /expression vector; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Tumor progression is angiogenesis dependent. Numerous antiangiogenic molecules have been described including fragments of endogenous proteins as well as small molecule inhibitors blocking proangiogenic signaling. These are in clinical development so that there is no currently approved FDA drug that is specifically antiangiogenic. We have "searched" for FDA approved compounds that may have antiangiogenic side effects, utilizing hints from the clinical and scientific literature, as well as suggestions on how to generate antiangiogenic protein fragments in vivo, thereby obviating the need to administer them. Our preliminary studies show that a cocktail of tissue plasminogen activator (tPA) and captopril generates potent in vitro and in vivo antiangiogenic effects, the latter in mice and in a patient with cancer. Moreover, the biological effects seen cannot be explained by the generation of angiostatin, a fragment of plasminogen, the original raison d'etre for this cocktail as proposed by Soft et al. During the course of these studies, we have discovered that thrombin has antiangiogenic activity. Laboratory and clinical extension of these findings constitutes the aims of this application. Aim 1: To test the anti-tumor efficacy of plasminogen activators and captopril in animal models Aim 2: To assess whether antiangiogenic activity can be safely generated in the blood of patients with advanced malignancies by administration of tPA and captopril Aim 3: To probe the molecular pathways by which thrombin exerts its antiangiogenic effect Aim 4: To purify the active antiangiogenic moiety from the blood of patients treated with tPA and captopril. These studies will set the stage for a Phase II trial of the tPA and captopril regimen for cancer therapy and perhaps for treating other angiogenesis dependent diseases as well.

描述（由申请人提供）：肿瘤进展依赖于血管生成。许多抗血管生成分子已被描述，包括内源性蛋白质片段以及阻断促血管生成信号的小分子抑制剂。这些都在临床开发中，所以目前还没有FDA批准的药物是专门抗血管生成的。我们已经“搜索”了FDA批准的可能具有抗血管生成副作用的化合物，利用临床和科学文献的提示，以及如何在体内产生抗血管生成蛋白片段的建议，从而避免了给药的需要。我们的初步研究表明，组织纤溶酶原激活剂（tPA）和卡托普利的混合物在体外和体内产生强大的抗血管生成作用，后者在小鼠和癌症患者中产生。此外，所见的生物学效应不能用血管抑制素（一种纤溶酶原片段）的产生来解释，而这是Soft等人提出的这种鸡尾酒存在的最初原因。在这些研究过程中，我们发现凝血酶具有抗血管生成活性。这些发现的实验室和临床扩展构成了本应用程序的目的。