TY - JOUR
T1 - Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy
AU - Armstrong, Leonard
AU - Arrington, Amanda
AU - Han, Joohee
AU - Gavrikova, Tatyana
AU - Brown, Eric
AU - Yamamoto, Masato
AU - Vickers, Selwyn M.
AU - Davydova, Julia
N1 - Funding Information:
Supported in part by the National Cancer Institute ( T32CA132715 to S.V., L.A.), by the National Cancer Institute ( P50CA101955 to J.D., S.V., M.Y.), by the National Cancer Institute ( R01CA094084 to M.Y., S.V., J.D.), and by the National Institute for Minority Health Disparities ( NIMHD/NIH-1P60MD003422 to S.V., J.H.).
PY - 2012/11
Y1 - 2012/11
N2 - Background: Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. Methods: Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. Results: Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. Conclusions: Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer-specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.
AB - Background: Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. Methods: Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. Results: Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. Conclusions: Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer-specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.
KW - Adenoviral death protein (ADP)
KW - Adenovirus
KW - Conditionally replicative adenovirus (CRAd)
KW - Cox2
KW - Gene therapy
KW - Interferon-alfa
KW - Krumdiek tissue slicer
KW - Oncolytic virus
KW - Pancreatic cancer
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U2 - 10.1016/j.amjsurg.2012.02.016
DO - 10.1016/j.amjsurg.2012.02.016
M3 - Article
C2 - 22748294
AN - SCOPUS:84868547011
SN - 0002-9610
VL - 204
SP - 741
EP - 750
JO - American Journal of Surgery
JF - American Journal of Surgery
IS - 5
ER -