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Evaluation of antiangiogenic role of EM011, a novel tubulin-binding agent

新型微管蛋白结合剂 EM011 的抗血管生成作用评估

基本信息

批准号：
8321603
负责人：
Ritu Aneja
金额：
$ 24.15万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-12 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321603
关键词：
Address Adhesions Angiogenesis Inhibitors Antineoplastic Agents Apoptosis Basement membrane Behavior Binding Biological Assay Blood Circulation Breast Cancer cell line Cell Culture Techniques Cell Cycle Progression Cell Line Cell Proliferation Cells Characteristics Combined Modality Therapy Computer software Cytoskeleton DNA DU145 Data Diagnostic Disease remission Dose Drug Combinations Endothelial Cells Evaluation Extracellular Matrix Gentian Violet Goals Hormone Receptor Human Image In Vitro Instruction Investigation Link MCF7 cell Malignant neoplasm of prostate Maximum Tolerated Dose Measures Mentors Methods Microtubules Neoplasm Metastasis Organ Outcome Pharmaceutical Preparations Phase Population Preclinical Drug Evaluation Procedures Property Prostate Proteins Quality of life Regimen Research Role Secondary to Side Site Staining method Stains T47D TdT-Mediated dUTP Nick End Labeling Assay Testing Thalidomide Therapeutic Time Toxic effect Transactivation Treatment Efficacy Tubulin Tubulin Binding Agent Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factors ZD-6474 angiogenesis annexin A5 base cancer cell cell motility combinatorial cytotoxicity depolymerization design in vivo indexing inhibitor/antagonist malignant breast neoplasm matrigel migration novel prevent quinoline research study response standard measure synergism time use translational approach tumor

项目摘要

Angiogenesis, necessary for tumor growtti involves cell proliferation and directed migration. Ttius, there is clearly a crucial role of cytoskeletal microtubule (MT) dynamics in angiogenesis; linking perturbations of MT dynamics to Inhibition of tumor angiogeneisis. Our preliminary data strongly suggest that a semisynthetic tubulin-binding anticancer agent,(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo[4,5- g]-iso-quinolin-5-yl)-6,7-dimethoxylsobenzofuran-1(3H)-one (EM011), has potent antiangiogenic activity (based upon NCI-DTP antiangiogenic drug screen). Our hypothesis is that EM011 will sen/e as an effective anticancer agent since it can target the MT cytoskeleton without causing any gross effects (over- or depolymerization of MTs) with concomitant antiangiogenic effects. The specific aims for the mentored phase were: Aim 1. Evaluation of the antiangiogenic efficacy of EM011. Aim 2. Determination of EM011's effect on the dynamic instability of MTs, HIF-lalpha expression and transactivation of downstream targets such as VEGF. We have successfully accomplished the proposed research in the K99 phase. Based upon the nontoxic attributes of EM011, we rationalize that combination of EM011 with other angiogenic inhibitors that function through independent mechanisms but show toxicity at their maximum tolerated doses (MTDs), presents a unique opportunity to reduce their doses to maximize therapeutic outcomes with decreased toxicity. The ROO phase of the project will focus on 2 aims: Aim 3. Investigation of potential synergistic antiproliferative and antiangiogenic effects of combinations of EM011 and ZD6474 (a tyrosine kinase inhibitor), or thalidomide (endothelial cell proliferation inhibitor) in breast (MDA-MB-231) and prostate (PC-3) cancer cells. Aim 4. Determination of the In vivo efficacy of EM011 and its synergistic combinations with ZD6474 or thalidomide, as inhibitors of experimental primary and metastatic breast and prostate cancers in real-time using non-invasive bioluminescent imaging.

肿瘤生长所必需的血管生成涉及细胞增殖和定向迁移。Ttius，有明确了细胞骨架微管（MT）动力学在血管生成中的关键作用; 抑制肿瘤血管生成的动力学。我们的初步数据有力地表明，微管蛋白结合抗癌剂，（S）-3-（（R）-9-溴-4-甲氧基-6-甲基-5，6，7，8-四氢-[1，3]-二氧杂环戊烯[4，5- g]-异喹啉-5-基）-6，7-二甲基异苯并呋喃-1（3 H）-酮（EM 011），具有有效的抗血管生成活性（基于NCI-DTP抗血管生成药物筛选）。我们的假设是EM 011将作为一种有效的抗癌剂，因为它可以靶向MT细胞骨架而不引起任何严重影响（过度或解聚的MT）具有伴随的抗血管生成作用。指导阶段的具体目标目标1。EM 011的抗血管生成功效的评价。目标二。确定EM 011对 MT的动态不稳定性、HIF-1 α表达和下游靶点的反式激活，血管内皮生长因子。我们已经成功地完成了K99阶段的拟议研究。基于无毒 EM 011的属性，我们合理化EM 011与其他血管生成抑制剂的组合，通过独立的机制发挥作用，但在其最大耐受剂量（MTD）下显示毒性，提供了一个独特的机会，以减少他们的剂量，以最大限度地提高治疗效果，毒性该项目的ROO阶段将侧重于两个目标：目标3。潜在协同效应的研究 EM 011和ZD 6474（一种酪氨酸激酶）组合的抗增殖和抗血管生成作用抑制剂）或沙利度胺（内皮细胞增殖抑制剂）在乳腺（MDA-MB-231）和前列腺（PC-3）癌细胞目标4。确定EM 011及其协同组合的体内功效 ZD 6474或沙利度胺作为实验性原发性和转移性乳腺癌和前列腺癌的抑制剂，实时使用非侵入性生物发光成像。