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: 6914912
• 负责人: VIKAS P SUKHATME
• 金额: $ 32.6万
• 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/6914912
• 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。已经描述了许多抗血管生成分子，包括内源蛋白片段以及阻断促血管生成信号传导的小分子抑制剂。这些药物正处于临床开发阶段，因此目前 FDA 还没有批准专门抗血管生成的药物。我们利用临床和科学文献中的提示以及如何在体内生成抗血管生成蛋白片段的建议，“搜索”了 FDA 批准的可能具有抗血管生成副作用的化合物，从而避免了施用它们的需要。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有效的抗血管生成作用，后者在小鼠和癌症患者中产生。此外，所看到的生物效应不能用血管抑制素（纤溶酶原片段）的产生来解释，血管抑制素是 Soft 等人提出的这种鸡尾酒的最初存在理由。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申请的目的。 目的1：在动物模型中测试纤溶酶原激活剂和卡托普利的抗肿瘤功效 目标 2：评估是否可以在患有以下疾病的患者的血液中安全地产生抗血管生成活性： tPA 和卡托普利治疗晚期恶性肿瘤 目标3：探讨凝血酶发挥抗血管生成作用的分子途径 目标 4：从接受 tPA 和卡托普利治疗的患者血液中纯化活性抗血管生成部分。这些研究将为 tPA 和卡托普利方案用于癌症治疗以及可能用于治疗其他血管生成依赖性疾病的 II 期试验奠定基础。