Potent antitumor efficacy of an E1B 55kDa-deficient adenovirus carrying murine endostatin in hepatocellular carcinoma.
Data from clinical trails have shown that the antitumoral effect of ONYX-015, an E1B 55kDa-deficient adenovirus, as monotherapy is insufficient. To enhance its efficiency, CNHK200-mE, another E1B 55kDa-deficient adenovirus armed with a mouse endostatin gene was constructed and its antitumoral activities against hepatocellular carcinoma (HCC) in vitro and in vivo were investigated. The selective replication and cytotoxicity of CNHK200-mE in Hep3B and HepGII cells independent of p53 status were confirmed via TCID50 and 3-(4,5dimetylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assays. Potent tumor growth suppression on SMMC-7721 xenografts in nude mice was observed and a synergistic effect of the carrier virus and the therapeutic gene was suggested. Moreover, in comparison with the nonreplicative adenovirus carrying the same therapeutic gene, amplified transgene expression of mouse endostatin in vitro and in vivo were confirmed by Western blotting and ELISA assay. The effective angiogenesis inhibition and replication of CNHK200-mE in nude mice xenografts were demonstrated by immunohistochemistry. In conclusion, the recombinant adenovirus CNHK200-mE is a replication-competent oncolytic virus mediating high expression of therapeutic gene. Because CNHK200-mE is capable of replicating in and lysing HCC cells selectively with effective tumor growth suppression and antiangiogenic activity on HCC xenografts in nude mice, it holds good potential for the treatment of HCC.
Li
Gencong
G
Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China.
Sham
Jonathan
J
Yang
Jiamei
J
Su
Changqing
C
Xue
Huibin
H
Chua
Daniel
D
Sun
Lichen
L
Zhang
Qi
Q
Cui
Zhenfu
Z
Wu
Mengchao
M
Qian
Qijun
Q
D000256:Adenoviridae / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000172:deficiency*; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000628:therapy* / Q000821:virology; D002470:Cell Survival / Q000187:drug effects; D043169:Endostatins / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D013778:Tetrazolium Salts; D013844:Thiazoles; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D043169:Endostatins; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue