SLT-VEGF for anti-angiogenic therapy of melanoma

SLT-VEGF 用于黑色素瘤的抗血管生成治疗

• 批准号: 6987676
• 负责人: CARL Venton HAMBY
• 金额: $ 13.42万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987676
• 关键词: angiogenesis inhibitors; antineoplastics; apoptosis; athymic mouse; cell growth regulation; chemical conjugate; clinical research; growth factor receptors; human subject; interferon alpha; melanoma; metastasis; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; shiga toxin; tissue /cell culture; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): The goal of this investigation is to assess the efficacy of a novel anti-angiogenic agent comprised of Shiga-like toxin A fused to vascular endothelial growth factor (SLT-VEGF) alone and in combination with another anti-angiogenic compound, IFN-alpha, in inhibiting the growth of human endothelial precursor cells in vitro and that of human melanoma tumors grown in nude mice. A pharmacological audit trail will be established in the proposed experiments to determine: 1) the presence of the SLT-VEGF target molecule, VEGF receptor-2 (KDR), on human endothelial cell colonies and in the vasculature of human melanoma tumors, 2) the degree of apoptosis induced by SLT-VEGF treatment alone and in combination with IFN-alpha, 3) the pharmacodynamic effects of SLT-VEGF alone and in combination with IFN-alpha on the IC50 of human endothelial precursor cells in vitro and 4) the biologic effects of SLT-VEGF alone and in combination with IFN-alpha on human melanoma tumor growth in vivo and on changes in serum levels of angiogenesis-related compounds. In addition the efficacy of SLT-VEGF alone and in combination with IFN-alpha in preventing metastatic disease will be assayed by treating mice whose primary melanoma tumor explants have been surgically removed. The information obtained in this study will provide a rational basis for deciding whether SLT-VEGF alone or combined with IFN-alpha will be suitable for further development and testing in clinical trials with human patients.

描述（由申请人提供）：本研究的目的是评估一种新型抗血管生成药物的功效，该药物由志贺样毒素a单独与血管内皮生长因子（SLT-VEGF）融合，并与另一种抗血管生成化合物ifn - α联合，在体外抑制人内皮前体细胞和裸鼠生长的人黑色素瘤肿瘤的生长。将在拟议的实验中建立药理学审计跟踪，以确定：1) SLT-VEGF靶分子VEGF受体-2 （VEGF receptor-2， KDR）在人内皮细胞菌落和人黑色素瘤血管中的存在；2)SLT-VEGF单独和联合ifn - α治疗诱导细胞凋亡的程度；3) SLT-VEGF单用及联用ifn - α对体外人内皮前体细胞IC50的药效学影响；4)SLT-VEGF单用及联用ifn - α对体内人黑色素瘤生长及血清血管生成相关化合物水平变化的生物学影响。此外，SLT-VEGF单独和与ifn - α联合在预防转移性疾病方面的功效将通过治疗手术切除原发性黑色素瘤肿瘤外植体的小鼠进行检测。本研究获得的信息将为SLT-VEGF单独使用或与ifn - α联合使用是否适合在人类患者的临床试验中进一步开发和测试提供合理的依据。