Targeting mesothelioma using an infectivity enhanced survivin-conditionally replicative adenoviruses.
Mesothelioma 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 is 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 clinical application of these CRAd agents; viral infectivity and tumor specificity have been poor. Herein we report on two CRAd agents, CRAd-S.RGD and CRAd-S.F5/3, 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 or F5/3) in the adenovirus fiber region. These CRAd agents effectively target human mesothelioma cell lines, induce strong cytoxicity in these cells in vitro, and viral replication in a H226 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 mesothelioma with low host toxicity. These agents should provide important insights into the identification of novel therapeutic strategies for mesothelioma.
Zhu
Zeng B
ZB
Department of Medicine, Pathology, and Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35291, USA.
Makhija
Sharmila K
SK
Lu
Baogen
B
Wang
Minghui
M
Wang
Shuyi
S
Takayama
Koichi
K
Siegal
Gene P
GP
Reynolds
Paul N
PN
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics; D017498:Adenovirus E1 Proteins / Q000235:genetics; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008099:Liver / Q000378:metabolism; D008654:Mesothelioma / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D050130:Oncolytic Virotherapy; D009924:Organ Culture Techniques; D010997:Pleural Neoplasms / Q000235:genetics / Q000628:therapy*; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D000077022:Survivin; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017498:Adenovirus E1 Proteins; C107489:BIRC5 protein, human; D036022:Capsid Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin