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

• 批准号: 8145705
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145705
• 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; HIF1A gene; 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; tumor growth

Angiogenesis, necessary for tumor growth involves cell proliferation and directed migration. Thus, 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 serve 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-1alpha 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.

血管生成是肿瘤生长所必需的，涉及细胞增殖和定向迁移。因此，有