Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor
Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor
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DOI：
10.1089/hum.1998.9.6-823
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发表时间：
1998-04-10
影响因子：
4.2
通讯作者：
Crystal, RG
中科院分区：
文献类型：
--
作者：
Kong, HL;Hecht, D;Crystal, RG
血管内皮生长因子（VEGF）是一种有效的血管生成介质，在大多数实体瘤中过表达。基于实体瘤生长超过一个小的体积是严重依赖于血管生成的知识，腺病毒（Ad）载体可以介导有效的体内基因转移和表达，我们假设，Ad介导的转移的分泌形式的细胞外结构域的flt-1 VEGF受体（Adsflt）将抑制肿瘤生长的区域的基础上。为了评估这一概念，使用鼠结肠癌细胞系和同基因BALB/c小鼠检查了三种肿瘤模型。首先，将预先建立的脾CT26.CL25肿瘤和肝转移瘤的小鼠静脉内给予AdsFlt/Adlectin，15天后，收获脾和肝以定量肿瘤负荷。Adslft治疗的动物具有最小的残留脾肿瘤和肝转移;相反，对照动物具有巨大的脾肿瘤和广泛的肝转移（p < 0.003）。第二，具有预先建立的肺转移的小鼠在区域性施用Adslft的情况下显示出肺转移的显著减少（静脉内，p < 0.02），但当载体全身性施用时没有（静脉内，p > 0.9）。最后，用肿瘤内施用Adslft治疗的具有原发性皮下肿瘤的小鼠显示出在AdNull-treated小鼠或静脉内给予Adslft的小鼠中未观察到的显著肿瘤抑制（p < 0.05）（p > 0.3）。我们的结论是，Ad介导的flt-1 VEGF受体胞外域分泌形式的体内区域递送可以有效抑制局部肿瘤生长，这一策略可能提供一种控制治疗器官内肿瘤生长的方法，而不会产生全身性抗血管生成的风险。
Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, is overexpressed in most solid tumors. On the basis of the knowledge that solid tumor growth beyond a small volume is critically dependent on angiogenesis, and that adenovirus (Ad) vectors can mediate efficient in vivo gene transfer and expression, we hypothesized that Ad-mediated transfer of a secreted form of the extracellular domain of the flt-1 VEGF receptor (Adsflt) would suppress tumor growth on a regional basis. To evaluate this concept, three tumor models were examined using a murine colon carcinoma cell line and syngeneic BALB/c mice. First, mice with preestablished splenic CT26.CL25 tumors and liver metastases were given Adsflt on AdNull intravenously and, after 15 days, spleens and livers were harvested to quantify tumor burden. Adslft-treated animals had minimal residual splenic tumors and liver metastases; in contrast, control animals had bulky splenic tumors and extensive liver metastases (p < 0.003). Second, mice with preestablished lung metastases showed a significant reduction in pulmonary metastases with regionally administered Adslft (intratracheal, p < 0.02) but not when the vector was systemically administered (intravenous, p > 0.9). Finally, mice with primary subcutaneous tumors treated with intratumoral administration of Adslft showed significant tumor suppression (p < 0.05) not observed in AdNull-treated mice or mice given Adslft intravenously (p > 0.3). We conclude that Ad-mediated in vivo regional delivery of a secreted form of the extracellular domain of the flt-1 VEGF receptor can effectively inhibit regional tumor growth, a strategy that may provide a means to control tumor growth within the treated organ without the risk of systemic antiangiogenesis.