TY - JOUR
T1 - Targeting lung cancer using an infectivity enhanced CXCR4-CRAd
AU - Zhu, Zeng B.
AU - Rivera, Angel A.
AU - Makhija, Sharmila K.
AU - Lu, Baogen
AU - Wang, Minghui
AU - Izumi, Miiru
AU - Cerfolio, Robert J.
AU - Stoff-Khalili, Mariam A.
AU - Zhou, Fen
AU - Takayama, Koichi
AU - Siegal, Gene P.
AU - Curiel, David T.
N1 - Funding Information:
Supported by the National Institute of Health Grants: R01 CA83821, R01 CA 94084, K12 HD01261-02, R01 HL67962 and R01 CA93796 and The Mesothelioma Applied Research Foundation, Inc.
PY - 2007/2
Y1 - 2007/2
N2 - Conventional treatments are not adequate for the majority of lung cancer patients. Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of neoplastic diseases, including non-small cell lung cancer. Specifically, following cellular infection, the virus replicates selectively in the infected tumor cells and kills the cells by cytolysis. Next, the progeny virions infect a new population of surrounding target cells, replicate again and eradicate the infected tumor cells while leaving normal cells unaffected. However, to date, there have been two main limitations to successful clinical application of these CRAd agents; i.e. poor infectivity and poor tumor specificity. Here we report the construction of a CRAd agent, CRAd-CXCR4.RGD, in which the adenovirus E1 gene is driven by a tumor-specific CXCR4 promoter and the viral infectivity is enhanced by a capsid modification, RGD4C. This agent CRAd-CXCR4.RGD, as expected, improved both of the viral infectivity and tumor specificity as evaluated in an established lung tumor cell line and in primary tumor tissue from multiple patients. As an added benefit, the activity of the CXCR4 promoter was low in human liver as compared to three other promoters regularly used for targeting tumors. In addition, this agent has the potential of targeting multiple other tumor cell types. From these data, the CRAd-CXCR4.RGD appears to be a promising novel CRAd agent for lung cancer targeting with low host toxicity.
AB - Conventional treatments are not adequate for the majority of lung cancer patients. Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of neoplastic diseases, including non-small cell lung cancer. Specifically, following cellular infection, the virus replicates selectively in the infected tumor cells and kills the cells by cytolysis. Next, the progeny virions infect a new population of surrounding target cells, replicate again and eradicate the infected tumor cells while leaving normal cells unaffected. However, to date, there have been two main limitations to successful clinical application of these CRAd agents; i.e. poor infectivity and poor tumor specificity. Here we report the construction of a CRAd agent, CRAd-CXCR4.RGD, in which the adenovirus E1 gene is driven by a tumor-specific CXCR4 promoter and the viral infectivity is enhanced by a capsid modification, RGD4C. This agent CRAd-CXCR4.RGD, as expected, improved both of the viral infectivity and tumor specificity as evaluated in an established lung tumor cell line and in primary tumor tissue from multiple patients. As an added benefit, the activity of the CXCR4 promoter was low in human liver as compared to three other promoters regularly used for targeting tumors. In addition, this agent has the potential of targeting multiple other tumor cell types. From these data, the CRAd-CXCR4.RGD appears to be a promising novel CRAd agent for lung cancer targeting with low host toxicity.
KW - Adenoviral vector
KW - CXCR4 gene
KW - Transcriptional targeting
KW - Tumor-specific promoter
UR - http://www.scopus.com/inward/record.url?scp=33846220985&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2006.10.012
DO - 10.1016/j.lungcan.2006.10.012
M3 - Article
C2 - 17113184
AN - SCOPUS:33846220985
SN - 0169-5002
VL - 55
SP - 145
EP - 156
JO - Lung Cancer
JF - Lung Cancer
IS - 2
ER -