IN VIVO GENERATION OF ANGIOSTATIN 4.5--CLINICAL TRIAL

血管抑制素 4.5 的体内生成——临床试验

• 批准号: 6514900
• 负责人: TIMOTHY M KUZEL
• 金额: $ 26.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514900
• 关键词: MESNA; angiostatins; clinical trial phase I; combination chemotherapy; drug administration rate /duration; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; paclitaxel; patient oriented research; pharmacokinetics; plasminogen activator; prostate neoplasms; renal cell carcinoma

For tumors to grow and metastasize, they must induce the generation of new blood vessels, a process referred to as angiogenesis. Inhibition of angiogenesis thus provides an important new therapeutic target. The angiogenesis inhibitor angiostatin is a kringle-containing internal fragment of plasminogen, which has been shown to inhibit cancer growth in numerous animal models. In previous R01-supported work at Northwestern University, Soff et al. have demonstrated the mechanism of generation of native human angiostatin. Plasminogen is first converted to plasmin by a plasminogen activator, and in the presence of a free sulfhydryl donor, plasmin undergoes autoproteolysis within kringle 5 to yield Angiostatin 4.5(AS4.5), consisting of the first 4 kringles as well as 85 percent of kringle 5. AS4.5 is present in normal and malignant blood and other specimens and is a potent inhibitor of angiogenesis and cancer growth in vivo. Of particular interest, in initial experiments in mice and humans with cancer, administration of an antiangiogenesis cocktail, consisting of a plasminogen activator and a free sulfhydryl donor results in marked increases in AS4.5 levels and inhibition of tumor growth. While ongoing work continues in better understanding the nature in vitro of AS4.5 activity, we are interested in more rigorously studying the in vivo generation of AS4.5 in human patients with advanced malignancies. The focus of this quick trial grant application is to determine in Phase I fashion the safe dosage range of drugs in the "cocktail," namely tissue plasminogen activator (tPA) and mesna. In addition, we will determine the dose response relationship of the agents in the antiangiogenesis cocktail with the levels of AS4.5. This will allow a rigorous calculation of the half-life, volume of distribution and area under the curve of this uniquely in vivo-generated anti-neoplastic therapy.

对于肿瘤的生长和转移，它们必须诱导 新血管的生成，这一过程被称为血管生成。 因此，抑制血管生成提供了重要的新治疗靶点。 血管生成抑制剂angiostatin是一种含有kringle的内源性 纤溶酶原片段，已被证明可以抑制癌症的生长， 许多动物模型。在以前的R01支持的工作在西北 University，Soff等人已经证明了天然的 人血管抑素。纤溶酶原首先被纤溶酶原转化为纤溶酶 激活剂，并且在游离巯基供体的存在下，纤溶酶经历 Kringle 5内的自身蛋白水解产生血管抑素4.5（AS 4.5），其由以下组成： 前4个kringle以及kringle 5的85%。AS4.5存在于 正常和恶性血液和其他标本，是一种有效的抑制剂， 血管生成和体内癌症生长。特别令人感兴趣的是， 在患有癌症的小鼠和人类中进行的实验， 抗血管生成鸡尾酒，由纤溶酶原激活剂和游离的 巯基供体导致AS 4.5水平显著增加， 肿瘤生长虽然正在进行的工作继续在更好地了解性质， 在体外的AS4.5活性，我们有兴趣更严格地研究 在患有晚期恶性肿瘤的人类患者中体内产生AS4.5。的 这一快速试验补助金申请的重点是确定在第一阶段的方式 安全剂量范围内的药物的“鸡尾酒”，即组织纤溶酶原 激活剂（tPA）和美司钠。此外，我们将确定剂量反应 抗血管生成鸡尾酒中的药剂与 AS4.5。这将允许严格计算半衰期， 分布和曲线下面积，这是唯一在体内产生的， 抗肿瘤治疗。