Enhanced sensitivity of hepatocellular carcinoma cells to chemotherapy with a Smac-armed oncolytic adenovirus  

作　　者：Qiu-wei PAN Su-yang ZHONG Bi-sheng LIU Jin LIU Rong CAI Yi-gang WANG Xin-yuan LIU Cheng QIAN 

机构地区：[1]Xin Yuan Institute of Medicine and Biotechnology, Life Science College, Zhejiang Sci-Tech University, Hangzhou 310018, China [2]Instituteof Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

出　　处：《Acta Pharmacologica Sinica》2007年第12期1996-2004,共9页中国药理学报（英文版）

基　　金：This work was supported by the 973 Project(№ 2004CB518804);the 863 project(№ 20060102Z1107);the Zhejiang Provincial Grant(№ 2006C23006);Zhejiang Funds for the Returned Students(№ 116153A410538);Zhejiang Natural Science Funds(№ Y205282)

摘　　要：Aim： The aim of the present study was to further improve the therapeutic effects for human hepatocellular carcinoma （HCC） and reduce the damage in normal cells using a novel chemo-gene-virotherapeutic strategy. Methods： An oncolytic adenoviral vector （ZD55） similar to the typical oncolytic adenovirus ONYX-015, with a deletion of E1B-55K gene, was employed to express the second mitochon- dria-derived activator of caspases （Smac） protein by constructing a recombinant virus ZD55-Smac. The enhanced cytotoxicity of the combined treatment of ZD55- Smac with cisplatin or 5-fluorouracil （5-FU） was evaluated in several HCC cell lines. Moreover, the negative effects on normal cells have been tested in human normal liver cell lines L-02 and QSG-7701 cell lines by 3-（4,5-dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide assay and apoptotic cell staining. Results： According to our observation, ZD55-Smac is superior to ONYX-015 in sensitizing chemotherapy, ZD55-Smac used in conjunction with chemotherapy was found to exhibit obviously enhanced cytotoxicity in HCC cells, yet significantly abolished the negative toxicity in normal cells by utilizing the tumor selective replication vector and reducing the dosage. Conclusion： This chemo-gene-virotherapeutic （cisplatin or 5-FU＋ZD55-Smac） strategy is superior to the conventional chemo- gene or chemo-viro approach.Aim： The aim of the present study was to further improve the therapeutic effects for human hepatocellular carcinoma （HCC） and reduce the damage in normal cells using a novel chemo-gene-virotherapeutic strategy. Methods： An oncolytic adenoviral vector （ZD55） similar to the typical oncolytic adenovirus ONYX-015, with a deletion of E1B-55K gene, was employed to express the second mitochon- dria-derived activator of caspases （Smac） protein by constructing a recombinant virus ZD55-Smac. The enhanced cytotoxicity of the combined treatment of ZD55- Smac with cisplatin or 5-fluorouracil （5-FU） was evaluated in several HCC cell lines. Moreover, the negative effects on normal cells have been tested in human normal liver cell lines L-02 and QSG-7701 cell lines by 3-（4,5-dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide assay and apoptotic cell staining. Results： According to our observation, ZD55-Smac is superior to ONYX-015 in sensitizing chemotherapy, ZD55-Smac used in conjunction with chemotherapy was found to exhibit obviously enhanced cytotoxicity in HCC cells, yet significantly abolished the negative toxicity in normal cells by utilizing the tumor selective replication vector and reducing the dosage. Conclusion： This chemo-gene-virotherapeutic （cisplatin or 5-FU＋ZD55-Smac） strategy is superior to the conventional chemo- gene or chemo-viro approach.

关 键 词：oncolytic adenovirus inhibitor of apoptosisproteins second mitochondria-derivedactivator of caspases CHEMOTHERAPY hepato-cellular carcinoma 

分 类 号：R735.7[医药卫生—肿瘤]