Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

Leonard Armstrong; Amanda Arrington; Joohee Han; Tatyana Gavrikova; Eric Brown; Masato Yamamoto; Selwyn M. Vickers; Julia Davydova

doi:10.1016/j.amjsurg.2012.02.016

Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

Leonard Armstrong, Amanda Arrington, Joohee Han, Tatyana Gavrikova, Eric Brown, Masato Yamamoto, Selwyn M. Vickers, Julia Davydova

Surgery

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	741-750
Number of pages	10
Journal	American journal of surgery
Volume	204
Issue number	5
DOIs	https://doi.org/10.1016/j.amjsurg.2012.02.016
State	Published - Nov 2012

Bibliographical note

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.).

Keywords

Adenoviral death protein (ADP)
Adenovirus
Conditionally replicative adenovirus (CRAd)
Cox2
Gene therapy
Interferon-alfa
Krumdiek tissue slicer
Oncolytic virus
Pancreatic cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{518be44b31874d0a8c7901f3f649cdb8,

title = "Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy",

abstract = "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.",

keywords = "Adenoviral death protein (ADP), Adenovirus, Conditionally replicative adenovirus (CRAd), Cox2, Gene therapy, Interferon-alfa, Krumdiek tissue slicer, Oncolytic virus, Pancreatic cancer",

author = "Leonard Armstrong and Amanda Arrington and Joohee Han and Tatyana Gavrikova and Eric Brown and Masato Yamamoto and Vickers, {Selwyn M.} and Julia Davydova",

note = "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.).",

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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

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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)

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KW - Gene therapy

KW - Interferon-alfa

KW - Krumdiek tissue slicer

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ER -

Generation of a novel, cyclooxygenase-2-targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

Abstract

Bibliographical note

Keywords

UN SDGs

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