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: 6570277
• 负责人: VIKAS P SUKHATME
• 金额: $ 31.06万
• 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/6570277
• 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）：肿瘤进展取决于血管生成。已经描述了许多抗血管生成分子，包括内源性蛋白质的片段以及封闭促血管生成信号传导的小分子抑制剂。这些是在临床发展中，因此目前尚无专门抗血管生成的批准的FDA药物。我们已经“搜索”了FDA批准的化合物，这些化合物利用了临床和科学文献的提示，以及有关如何在Vivo中产生抗血管生成蛋白片段的建议，从而避免了对它们进行管理的需求。我们的初步研究表明，组织纤溶酶原激活剂（TPA）和卡托普利的鸡尾酒会产生有效的体外和体内抗血管生成作用，后者在小鼠和癌症患者中产生。此外，所看到的生物学作用无法通过Soft等人提出的这种鸡尾酒的原始Raison d'Etre产生，纤溶酶原的片段（纤溶酶原的碎片）无法解释。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的目的。 目标1：测试纤溶酶原激活剂和卡托普利在动物模型中的抗肿瘤功效 目标2：评估是否可以在患者的血液中安全地产生抗血管生成活性 TPA和Capteropril的管理高级恶性肿瘤 目标3：探测凝血酶发挥其抗血管生成作用的分子途径 目标4：从用TPA和卡托普利治疗的患者的血液中纯化活性抗血管生成部分。这些研究将为癌症治疗的TPA和卡托普利方案的II期试验奠定了基础，也许还可以治疗其他血管生成依赖性疾病。