Ad-KDRscFv:sTRAIL displays a synergistic antitumor effect without obvious cytotoxicity to normal tissues

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• 作者：Liuqin Yang¹ ; Jun Guo¹ ; Jun Wang ; Shunmei Wan ; Shiming Yang ; Rongquan Wang ; Wensheng Chen ; Guiyong Peng ; Dianchun Fang ; ^{fangdianchun@hotmail.com}
• 关键词：KDRscFv ; TRAIL ; Gene fusion ; Replication-defective ; Recombinant adenovirus
• 刊名：International Immunopharmacology
• 出版年：2012
• 期刊代码：123_15675769
• 类别：med
• 出版时间：May, 2012
• 卷：13
• 期：1
• 页码：37-45
• 文件大小：1720 K

摘要

Aim

To investigate the antitumor activities and safety of Ad-KDRscFv, Ad-sTRAIL (114-281) and Ad-KDRscFv:sTRAIL in vivo and in vitro.

Methods

Recombinant replication-defective adenovirus vectors encoding either the extracellular domain (114-281 aa) of TRAIL, the KDRscFv (single chain antibody (scFv) against human vascular endothelial growth factor (VEGF) receptor KDR) or the fusion gene of KDRscFv:sTRAIL were constructed and transfected into HEK 293 cells for virus packaging. The recombinant virus particles were then infected human tumor cell lines of liver cancer (HepG2), gastric cancer (SGC-7901), colorectal cancer (SW480) and normal human liver cell line (LO2) to investigate the antitumor activities. Nude mice of the subcutaneous tumor models were established with HepG2 cells and were randomly divided into different groups to investigate the therapeutic effect and safety of these adenovirus particles on hepatocellular carcinoma. The expression of foreign proteins and the effect on microvascular number were also evaluated.

Results

All three adenovirus particles could induce apoptosis of cancer cells lines HepG2, SGC-7901 and SW480, but had no obvious lethal effect on LO2 cells. Ad-KDRscFv:sTRAIL showed the strongest tumoricidal effect. After intratumoral injection with these adenovirus particles on nude mice model, all the three adenoviruses could inhibit the tumor growth and angiogenesis, and the expression of foreign proteins (sTRAIL, KDRscFv and KDRscFv:sTRAIL fusion protein) was restricted to liver and tumor tissues. In coincidence with the result in vitro, Ad-KDRscFv:sTRAIL also had the strongest antitumor activity in vivo. No obvious pathological changes were detected in vivo.

Conclusions

Replication-defective recombinant adenovirus of Ad-KDRscFv, Ad-sTRAIL and Ad-KDRscFv:sTRAIL all had tumoricidal activities and Ad-KDRscFv:sTRAIL showed the strongest effect. All three adenoviruses had no obvious toxicity to normal cells and tissues in vitro and in vivo.