OVARIAN CANCER ANTI ANGIOGENIC FACTOR

卵巢癌抗血管生成因子

• 批准号: 6132950
• 负责人: VIKAS P SUKHATME
• 金额: $ 17.4万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6132950
• 关键词: affinity chromatography; angiogenesis inhibitors; ascites; athymic mouse; cyclin dependent kinase; cyclins; growth media; human tissue; ion exchange chromatography; ovary neoplasms; protein purification

Anti-angiogenic therapy promises to be a powerful tool for the treatment of solid tumors: drug resistance is less likely to develop and such therapy may be effective in a broad range of tumor types. A diverse array of compounds have been described which possess anti-angiogenic action. The subclass of these that are proteins have attracted considerable attention because of their ability to regress tumors. These have also turned out to be fragments of naturally occurring proteins. However, certain limitations exist for the use of these known proteins for therapy; namely, that delivery cannot be oral, and that large amounts are currently needed for efficacy. With regard to the latter, there is, therefore, a need to identify compounds with greater potency. This proposal focuses on the isolation and initial characterization of factors derived from human ovarian cancer ascites and conditioned medium (CM) from an ovarian cancer cell line. In preliminary studies, the PI has identified a gel filtration fraction of this ascites and CM, which shows remarkable activity towards endothelial cells in both proliferation and migration assays. The activity is heat and protease labile, suggesting that it is a protein. Furthermore, this activity is at least a 1000 fold more potent than endostatin. Specific Aim 1: Purification of anti-angiogenic agent from ovarian cancer CM Specific Aim 2: Functional characterization of the anti-angiogenic agent(s) These findings may have major therapeutic implications, in that they will provide an alternative source for powerful anti-angiogenic compounds. Moreover, an understanding of the mechanism of action will allow for the optimal and rational use in tumor therapy, in combination with other angiostatic agents or chemo- or radiation therapy. Such agents would be useful not only in tumor therapy, but in other angiogenesis dependent disease states, as well.

抗血管生成疗法有望成为实体瘤治疗的有力工具：耐药性不太可能发展，这种疗法可能在广泛的肿瘤类型中有效。 已经描述了具有抗血管生成作用的各种化合物。这些蛋白质的子类吸引了大量关注，因为它们能够回归肿瘤。事实证明，这些是天然存在的蛋白质的碎片。但是，使用这些已知蛋白质进行治疗存在某些局限性。也就是说，这种交付不能是口头，目前需要大量疗效。因此，关于后者，有必要以更大的效力识别化合物。该提案的重点是源自卵巢癌腹水和条件培养基（CM）的因素的隔离和初始表征。 在初步研究中，PI鉴定了该腹水和CM的凝胶过滤部分，在增殖和迁移测定中，对内皮细胞的活性显着。活性是热和蛋白酶不稳定的，表明它是一种蛋白质。此外，该活动至少比内胞霉素高1000倍。特定目的1：卵巢癌CM特异性目标的抗血管生成剂2：抗血管生成剂的功能表征这些发现可能具有重大的治疗意义，因为它们将为强大的抗血管生成化合物提供替代来源。此外，了解作用机理将允许与其他血管抑制剂或化学或放射治疗结合使用肿瘤治疗中的最佳和合理使用。这种药物不仅在肿瘤疗法中也有用，而且在其他依赖性疾病状态中也将是有用的。