Angiostatin gene transfer:: Inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest
Angiostatin gene transfer:: Inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest
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DOI：
10.1073/pnas.95.11.6367
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Lu, H
中科院分区：
文献类型：
--
作者：
Griscelli, F;Li, H;Lu, H
已在两种异种移植鼠模型中研究了人纤溶酶原（血管抑制素 K3）N 末端片段局部递送后的抗肿瘤作用。血管抑制素的递送是通过有缺陷的腺病毒实现的，该腺病毒从巨细胞病毒启动子（AdK3）表达可分泌的血管抑制素K3分子。在体外研究中，AdK3 选择性抑制内皮细胞增殖并破坏 M 期促进因子诱导的 G(2)/M 转变。 AdK3 感染的内皮细胞表现出明显的有丝分裂停滞，这与 M 期磷蛋白的下调相关。将 AdK3 单次瘤内注射到预先建立的大鼠 C6 神经胶质瘤或在无胸腺小鼠中生长的人 MDA-MB-231 乳腺癌中，随后肿瘤生长显着停滞，这与肿瘤内部和附近的新血管形成的抑制有关。与对照腺病毒相比，AdK3 疗法还诱导肿瘤细胞凋亡增加 10 倍。此外，我们发现全身注射 AdK3 可以延迟 C6 肿瘤的形成和生长，证实血管抑制素可以以旁分泌方式发挥作用。我们的数据支持这样的概念，即使用腺病毒介导的基因转移来靶向抗血管生成，代表了一种有前途的传递抗血管生成因子的替代策略，因为它们的推注存在未解决的药理学问题。
The antitumoral effects that follow the local delivery of the N-terminal fragment of human plasminogen (angiostatin K3) have been studied in two xenograft murine models. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule from the cytomegalovirus promoter (AdK3). In in vitro studies, AdK3 selectively inhibited endothelial cell proliferation and disrupted the G(2)/M transition induced by M-phase-promoting factors. AdK3-infected endothelial cells showed a marked mitosis arrest that correlated with the downregulation of the M-phase phosphoproteins. A single intratumoral injection of AdK3 into preestablished rat C6 glioma or human MDA-MB-231 breast carcinoma grown in athymic mice was followed by a significant arrest of tumor growth, which was associated with a suppression of neovascularization within and at the vicinity of the tumors. AdK3 therapy also induced a 10-fold increase in apoptotic tumor cells as compared with a control adenovirus. Furthermore, we showed that systemic injection of AdK3 delayed C6 tumor establishment and growth, confirming that angiostatin can function in a paracrin manner. Our data support the concept that targeted antiangiogenesis, using adenovirus-mediated gene transfer, represents a promising alternative strategy for delivering antiangiogenic factors as their bolus injections present unsolved pharmacological problems.