SLT-VEGF for anti-angiogenic therapy of melanoma

描述(申请人提供)：本研究的目的是评价一种新型的抗血管生成药物，该药物由志贺样毒素A与血管内皮生长因子融合(SLT-VEGF)组成，并与另一种抗血管生成化合物干扰素-α联合使用，在体外抑制人内皮前体细胞的生长，并抑制人黑色素瘤在裸鼠体内的生长。在拟议的实验中，将建立一项药理学审计线索，以确定：1)SLT-VEGF靶分子-VEGF受体-2(KDR)在人内皮细胞集落和人黑色素瘤血管系统中的存在，2)SLT-VEGF单独治疗和联合干扰素-α治疗诱导的凋亡程度，3)SLT-VEGF单独及联合干扰素-α对体外培养的人内皮祖细胞IC50的药效学作用；4)SLT-VEGF单独及联合应用对人黑色素瘤体内生长的影响及对血清血管生成相关化合物水平的影响。此外，SLT-VEGF单独和联合干扰素-α预防转移疾病的有效性将通过治疗其原发黑色素瘤外植体已被手术切除的小鼠来进行评估。本研究获得的信息将为决定SLT-VEGF单独或联合干扰素-α是否适合于在人类患者的临床试验中进一步开发和测试提供合理的基础。

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.