Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma.
Cholangiocarcinoma is a highly malignant neoplasm with no effective treatment. Conditionally replicative adenoviruses (CRAds) represent a promising new modality for the treatment of cancer in general. A key contribution in this regard was the introduction of tumor-selective viral replication for amplification of the initial inoculum in the neoplastic cell population. Under ideal conditions following cellular infection, the viruses replicate selectively in the infected tumor cells and kill the cells by cytolysis, leaving normal cells unaffected. However, to date there have been two limitations to the clinical application of these CRAd agents, i.e. poor viral infectivity and tumor specificity. Here we report the construction of three new CRAd agents, CRAd-S.RGD, CRAd-S.F5/3 and CRAd-S.pk7, in which the tumor specificity is regulated by a tumor-specific promoter, the survivin promoter, and the viral infectivity is enhanced by incorporating a capsid modification (RGD, F5/3 or pk7) in the adenovirus fiber region. These CRAd agents effectively target cholangiocarcinoma cells, induce strong cytoxicity in these cells in vitro and inhibit tumor growth in a murine xenograft model in vivo. In addition, the survivin promoter has extremely low activity both in the non-transformed cell line, HMEC, and in human liver tissue. Our results suggest that the survivin-based CRAds are promising agents for targeting cholangiocarcinoma with low host toxicity. Such results should provide important insights into the identification of novel therapeutic strategies for cholangiocarcinoma.
Zhu
Zeng Bian
ZB
Division of Human Gene Therapy, Department of Medicine, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35291, USA.
Chen
Yabing
Y
Makhija
Sharmila K
SK
Lu
Baogen
B
Wang
Minghui
M
Rivera
Angel A
AA
Yamamoto
Masato
M
Wang
Shuyi
S
Siegal
Gene P
GP
Curiel
David T
DT
McDonald
Jay M
JM
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000628:therapy*; D002213:Capsid / Q000378:metabolism; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000235:genetics / Q000628:therapy*; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D050130:Oncolytic Virotherapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D000077022:Survivin; D014779:Virus Replication / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin