INHIBITION OF HEPARIN-BINDING GROWTH FACTORS

抑制肝素结合生长因子

• 批准号: 3201745
• 负责人: Anton Wellstein
• 金额: $ 16.5万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-07 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3201745
• 关键词: analog; athymic mouse; cell cycle; clinical trials; drug design /synthesis /production; drug screening /evaluation; fibroblast growth factor; gene expression; growth inhibitors; heparin; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplastic growth; neoplastic transformation; polymerase chain reaction; prognosis; prostate neoplasms; racial /ethnic difference

Inhibition of Heparin-Binding Growth Factors. Sustained prostate cancer growth and metastasis requires paracrine signals between the tumor cells and the normal surrounding host tissue. One crucial function of these signals is to recruit endothelial cells and thus new blood vessels for the nourishment of the expanding tumor mass. This proliferation and migration of endothelial cells in the vicinity of progressing tumors con- trasts with the extremely low turn-over rate of endothelial cells in the healthy adult. Thus, a selective blockade of the tumor-induced endothelial cell proliferation should inhibit tumor growth and potentially metastasis with only few adverse effects. We found that the most effective endothelial cell growth factors released from prostate cancer cells in vitro are heparin-binding growth factors (HBGFs) and we have therefore focused our search for inhibitors on heparin-like polysulfates. We have demonstrated that HBGF action in vitro can be blocked by a structural analogue of heparin: pentosanpolysulfate (PPS). Furthermore, the growth of human prostate cancer cell lines into tumors in athymic nude mice can be inhibited by the treatment of the animals with PPS. PPS was effective against tumors derived from in vitro PPS-sensitive and from in vitro PPS-resistant tumor cell lines. This data suggests that PPS blocks the hosts' reaction to the HBGF(s) released from the tumor cells. We propose the following studies: 1. To study the efficacy of PPS in a Phase II trial with prostate cancer patients. In an ongoing Phase I trial with PPS in patients with advanced cancer, we will determine a dose schedule that is safe and maintains continuously high concentrations of biologically active drug in the patients. 2. To develop new synthetic heparinoids as HBGF-inhibitors in vitro and in vivo. In particular, to find analogues with improved therapeutic index. 3. To determine to what extent endothelial cell proliferation in normal, hypertrophic and cancerous prostate tissue can serve as an indicator of the disease state, prognosis of the patient and responsiveness to therapy. 4. To probe for expression of known HBGF genes in normal, hypertrophic and cancerous prostate tissue as potential markers of the progression and prognosis of the disease as well as therapeutic response to the HBGF-targeted therapy. An important aspect of our studies is to analyze the results according to the ethnic origin of the patients. This should enable us to detect differences in the biological and molecular markers and thus understand differences in the prognosis and therapeutic responsiveness of prostate cancer.

抑制肝素结合生长因子。持续性前列腺癌 生长和转移需要肿瘤细胞间的旁分泌信号 以及周围正常的宿主组织。它们的一个重要功能是 Signals是招募内皮细胞，从而为 不断膨胀的肿块的滋养。这种扩散和 进展期肿瘤周围血管内皮细胞的迁移 与极低的内皮细胞周转率作斗争 健康的成年人。因此，选择性阻断肿瘤诱导的 内皮细胞增殖应抑制肿瘤生长和 潜在的转移，只有很少的副作用。 我们发现，最有效的内皮细胞生长因子释放 来自体外前列腺癌细胞的是肝素结合生长因子 (HBGFs)，因此我们将寻找抑制剂的重点放在 类肝素多硫酸盐。我们已经证明了HBGF在 体外培养可被肝素的结构类似物阻断： 戊聚硫酸酯(PPS)。此外，人类前列腺的生长 肿瘤细胞株在裸鼠体内的生长可被抑制 PPS对动物的治疗。PPS对肿瘤有效 来源于体外PPS敏感和耐药肿瘤 细胞系。这一数据表明，PPS阻止了宿主对 从肿瘤细胞中释放出HBGF(S)。 我们提出了以下研究建议：1.研究PPS在老年患者中的疗效。 前列腺癌患者的II期试验。在正在进行的第一阶段 对晚期癌症患者进行PPS试验，我们将确定剂量 安全并持续保持较高浓度的 患者体内的生物活性药物。2.开发新的合成材料 肝素类化合物作为HBGF的体外和体内抑制剂。尤其是， 寻找治疗指数更高的类似物。3.确定要做什么 正常、肥厚性血管内皮细胞增殖程度 前列腺癌组织可以作为疾病状态的指示器， 患者的预后和对治疗的反应。4.探寻 已知HBGF基因在正常、肥大及癌组织中的表达 前列腺组织作为前列腺癌进展和预后的潜在标记物 疾病以及对HBGF靶向治疗的治疗反应。 我们研究的一个重要方面是根据以下因素分析结果 病人的种族血统。这应该使我们能够检测到 生物和分子标记的差异，从而理解 前列腺癌预后和治疗反应的差异 癌症。