SLT-VEGF for anti-angiogenic therapy of melanoma

描述（由申请人提供）：本研究的目的是评估由融合至血管内皮生长因子（SLT-VEGF）的志贺样毒素A组成的新型抗血管生成剂单独以及与另一种抗血管生成化合物IFN-α组合在体外抑制人内皮前体细胞生长和在裸鼠中生长的人黑素瘤肿瘤生长方面的功效。将在拟定实验中建立药理学稽查跟踪，以确定：1）人内皮细胞集落上和人黑素瘤肿瘤的脉管系统中SLT-VEGF靶分子VEGF受体-2（KDR）的存在，2）单独和与IFN-α组合的SLT-VEGF处理诱导的细胞凋亡的程度，3）单独的SLT-VEGF和与IFN-α组合对体外人内皮前体细胞的IC 50的药效学作用，和4）单独的SLT-VEGF和与IFN-α组合的SLT-VEGF的生物学作用。α对体内人黑色素瘤肿瘤生长和血管生成相关化合物血清水平变化的影响。此外，将通过治疗其原发性黑色素瘤肿瘤外植体已被手术移除的小鼠来测定SLT-VEGF单独和与IFN-α组合在预防转移性疾病中的功效。本研究中获得的信息将为决定SLT-VEGF单独或与IFN-α组合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.