Maximization of anti-angiogenesis by thrombospondin-1

血小板反应蛋白-1 最大限度地抑制血管生成

• 批准号: 6969494
• 负责人: OLGA Valery VOLPERT
• 金额: $ 28.67万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969494
• 关键词: angiogenesis inhibitors; antineoplastics; apoptosis; cell line; cell surface receptors; combination cancer therapy; confocal scanning microscopy; drug screening /evaluation; flow cytometry; growth inhibitors; human tissue; immunocytochemistry; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; neoplastic growth; neutralizing antibody; peroxisome proliferator activated receptor; protein structure function; receptor binding; receptor expression; statistics /biometry; terminal nick end labeling; thiazoles; thrombospondins; vascular endothelium

DESCRIPTION (provided by applicant): Anti-angiogenic thrombospondin-1 (TSP1) binds CD36 receptor to trigger apoptosis in vascular endothelium. This causes a secondary signal via CD95/Fas, a death receptor expressed independent of TSP1 by remodeling endothelium. TSP1 increases CD95 cognate ligand, FasL, which binds inducer-generated Fas causing apoptosis. DI-TSP, a short TSP-derived inhibitory peptide generates identical signal. Thus the sensitivity to inhibitory TSP1/DI-TSP is limited by the availability of its primary (CD36), or secondary (CD95) signaling receptors. We aim to improve susceptibility to DI-TSP by modulating the levels of these rate-limiting signaling mediators. We will modulate CD36 using synthetic ligands of the PPARy nuclear receptor. CD95 we will alter with low-dose continuous (metronomic) chemotherapy. We propose to study: 1. The effects of the low-dose genotoxic agents on DI-TSP specific activity. We will measure Fas and FasL in human microvascular cells (HMVECs) treated with DI-TSP and/or low dose chemotherapy and compare the effects of DI-TSP and/or chemotherapy on the endothelial (EC) and cancer cell phenotype, Fas and FasL presentation, apoptosis and migration. Antibodies, Fas decoy receptor and metabolic inhibitors will be used to link CD95 increase with TSP1 augmented activity. 2. The effects of metronomic chemotherapy DI-TSP angiosuppression in vivo. Mice bearing bFGF-containing Matrigel plugs will be treated with DI-TSP and/or metronomic chemotherapy. The effect on vascularity, Fas and FasL expression, the extent of endothelia l cell apoptosis and pericyte recruitment will be measured. Antibodies, Fas decoy receptor and metabolic inhibitors will be used to link CD95 increase with TSP1 augmented activity. 3. The effects of thiazolinediones (TZDs, synthetic PPARy ligands) on CD36 expression and TSP1 anti-angiogenic activity. EC apoptosis, inhibition of migration, proliferation will be used to determine non-cytotoxic doses of troglitazone, rosiglitazone and pioglitazone, to achieve maximal CD36 increase. These doses will be tested in vivo in matrigel plug assay. CD36 neutralizing antibodies will be used to determine its contribution in vitro and in vivo. 4. The effect of TSP-based combination therapies on tumor growth and angiogenesis. TZDs and metronomic chemotherapy will be used alone and in combination with DI-TSP to block or delay the growth of invasive PC-3 or of less aggressive LNCaP prostate carcinoma. Tumor volume, angiogenesis, EC and non-EC apoptosis will be measured. Angiogenesis inhibitors comprise a new class of anti-cancer drugs. We showed that combining anti-angiogenics with chemotherapy offers possibility to significantly cut the dose and therefore the toxicity of chemotherapy while achieving substantial improvement in the efficacy of an anti-angiogenic. Such combined therapies present a promising new approach to the treatment of cancer and other angiogenesis dependent diseases.

描述（由申请人提供）：抗血管生成的血小板素-1（TSP1）结合CD36受体以触发血管内皮细胞凋亡。这会导致通过CD95/FAS的次级信号，CD95/FAS是一种通过重塑内皮而独立于TSP1表示的死亡受体。 TSP1增加了CD95同源配体FASL，该配体结合诱导者生成的FA，引起凋亡。 DI-TSP，短TSP衍生的抑制性肽会产生相同的信号。因此，对抑制性TSP1/DI-TSP的敏感性受其主要（CD36）或次级（CD95）信号受体的可用性的限制。我们旨在通过调节这些限制信号传导介质的水平来提高对DI-TSP的敏感性。我们将使用PPARY核受体的合成配体调节CD36。 CD95我们将使用低剂量连续（计量）化学疗法进行改变。我们建议研究：1。低剂量基因毒性剂对DI-TSP特异性活性的影响。我们将测量用DI-TSP和/或低剂量化学疗法治疗的人类微血管细胞（HMVEC）中的FA和FASL，并比较DI-TSP和/或化学疗法对内皮（EC）以及癌细胞表型，FAS和FAS的影响，FAS和FASL表现，凋亡和凋亡和迁移的影响。抗体，FAS诱饵受体和代谢抑制剂将用于将CD95增加与TSP1增强活性联系起来。 2。在体内di-tspSpSpspression di-tsp Sps抑制的影响。携带含BFGF母质塞的小鼠将用DI-TSP和/或监测化疗治疗。将测量对血管性，FAS和FASL表达的影响，内皮L细胞凋亡和周围募集的程度。抗体，FAS诱饵受体和代谢抑制剂将用于将CD95增加与TSP1增强活性联系起来。 3。噻唑酚（TZDS，合成配体）对CD36表达和TSP1抗血管生成活性的影响。 EC凋亡，抑制迁移，增殖将用于确定troglitazone，Rosiglitazone和Pioglitazone的非毒性剂量，以实现最大的CD36。这些剂量将在Matrigel插头测定中在体内进行测试。 CD36中和抗体将用于确定其体外和体内的贡献。 4。基于TSP的组合疗法对肿瘤生长和血管生成的影响。 TZD和计量化疗将单独使用，并与DI-TSP结合使用，以阻止或延迟侵入性PC-3或攻击性LNCAP前列腺癌的生长。将测量肿瘤体积，血管生成，EC和非EC凋亡。血管生成抑制剂包括一类新的抗癌药物。我们表明，将抗血管生成与化学疗法结合起来，可以显着减少剂量，因此可以显着减少化学疗法的毒性，同时实现抗血管生成的疗效的实质性提高。这种综合疗法为癌症和其他血管生成疾病的治疗提供了一种有希望的新方法。