A truncated minimal-E1a

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• 作者：Lin Fang ; Yao Huang ; Xiaocui Hu ; Lijun Sun ; Xiaoping He ; Huanzhang Hu ; Yingyan Pu ; Xiangrong Cao ; Hongmei Luo ; Shaokun Pan ; Jianzhong Gu ; Changqing Su
• 关键词：Oncolytic adenovirus ; E1a gene ; Neu gene ; Rb gene ; Cancer gene therapy
• 刊名：Chemico-Biological Interactions
• 出版年：2009
• 出版时间：14 September 2009
• 年：2009
• 卷：181
• 期：1
• 页码：1-7
• 全文大小：854 K

文摘

Oncolytic adenovirus is capable of infecting, replicating in and lysing cancer cells. In adenovirus infection and replication, the wild type E1a gene (wE1a) mediates various genetic events to facilitate viral replication and exert antitumor effect. To enhance its antitumor efficacy and optimize its safety, we manipulated the wE1a gene and designed a 720-bp truncated minimal-E1a (mE1a) by deletions and mutations of amino acid residues. The mE1a gene was incorporated in an adenovirus under the control of hTERT promoter, giving the vector AdDC315-mE1a. A variety of cancer cell lines infected with the virus expressed the mE1a protein and showed considerable down-regulation in Neu protein expression as compared to normal cell lines. mE1a also had a lower binding affinity to the Rb protein, preserving the Rb tumor suppressive function. The mE1a expression allowed efficient adenovirus replication with high and stable replication ratios in cancer cells (about 125- to 8500-fold higher at 48 h and 180- to 10,900-fold higher at 96 h post-infection). Further, the mE1a-supported oncolytic adenovirus induced higher cancer cell apoptosis, stronger cell cycle arrest and more effective antitumor efficacy in hepatocarcinoma xenografts in nude mice. In conclusion, the truncated minimal mE1a can act as a tumor inhibitor gene, and may be used to construct oncolytic adenovirus vectors for use in gene therapy of a variety of cancers.