TY - JOUR
T1 - Targeting mesothelioma using an infectivity enhanced survivin-conditionally replicative adenoviruses
AU - Zhu, Zeng B.
AU - Makhija, Sharmila K.
AU - Lu, Baogen
AU - Wang, Minghui
AU - Wang, Shuyi
AU - Takayama, Koichi
AU - Siegal, Gene P.
AU - Reynolds, Paul N.
AU - Curiel, David T.
PY - 2006/9
Y1 - 2006/9
N2 - 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.
AB - 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.
KW - Adenoviral vector and mesothelioma
KW - Survivin gene
KW - Transcriptional targeting
KW - Tumor-specific promoter
UR - http://www.scopus.com/inward/record.url?scp=34247893974&partnerID=8YFLogxK
U2 - 10.1016/s1556-0864(15)30385-3
DO - 10.1016/s1556-0864(15)30385-3
M3 - Article
C2 - 17409940
AN - SCOPUS:34247893974
SN - 1556-0864
VL - 1
SP - 701
EP - 711
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 7
ER -