Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2
Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2
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DOI：
10.1073/pnas.95.15.8829
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发表时间：
1998-07-21
影响因子：
11.1
通讯作者：
Peters, KG
中科院分区：
文献类型：
--
作者：
Lin, PN;Buxton, JA;Peters, KG
血管生成是肿瘤生长和转移所必需的，抑制血管生成是一种有前途的抗癌治疗方法，Tie 2（a. k. aTek）是已知在肿瘤血管生成中起作用的内皮特异性受体酪氨酸激酶。为了探索阻断Tie 2途径的治疗潜力，构建腺病毒载体以递送重组，能够阻断Tie 2激活的可溶性Tie 2受体（AdExTek）。静脉注射AdExTek后两天，ExTek的血浆浓度超过1 mg/ml，并维持约8天。向具有两种不同的良好建立的原发性肿瘤（鼠乳腺癌（4 T1）或鼠黑色素瘤（B16F10.9））的小鼠施用AdExTek显著抑制两种肿瘤的生长速率（分别为64%和47%）。为了研究ExTek对肿瘤转移的作用，将两种肿瘤细胞系与AdExTek或对照病毒一起静脉内共注射。与对照病毒共注射的小鼠发展了许多大的、血管化良好的肺转移。相比之下，与AdExTek病毒共注射的小鼠发展了很少的（如果有的话）大体上明显的转移，并且组织学检查仅揭示了小的无血管肿瘤细胞簇。在临床相关的肿瘤转移模型中，当在手术切除原发性肿瘤时递送时，AdExTek的施用也抑制肿瘤转移。这项研究表明，潜在的效用基因治疗系统交付的抗血管生成剂靶向内皮特异性受体，Tie 2。
Angiogenesis is required for tumor growth and metastasis, and inhibition of angiogenesis is a promising approach for anticancer therapy, Tie2 (a.k.a Tek) is an endothelium-specific receptor tyrosine kinase known to play a role in tumor angiogenesis, To explore the therapeutic potential of blocking the Tie2 pathway, an adenoviral vector was constructed to deliver a recombinant, soluble Tie2 receptor (AdExTek) capable of blocking Tie2 activation. Two days after i.v. injection of AdExTek, the plasma concentration of ExTek exceeded 1 mg/ml and was maintained for about 8 days. Administration of AdExTek to mice with two different well established primary tumors, a murine mammary carcinoma (4T1) or a murine melanoma (B16F10.9), significantly inhibited the growth rate of both tumors (64% and 47%, respectively), To study the effect of ExTek on tumor metastasis, both tumor cell lines were coinjected i.v. with either AdExTek or a control virus. Mice coinjected with control virus developed numerous large, well vascularized lung metastases, In contrast, mice coinjected with AdExTek virus developed few, if any, grossly apparent metastases, and histologic examination revealed only small avascular clusters of tumor cells, Administration of AdExTek also inhibited tumor metastasis when delivered at the time of surgical excision of primary tumors in a clinically relevant model of tumor metastasis. This study demonstrates the potential utility of gene therapy for systemic delivery of an antiangiogenic agent targeting an endothelium-specific receptor, Tie2.