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

被引：25

作者：

Armstrong, Leonard ^{[1
]}

Arrington, Amanda ^{[1
]}

Han, Joohee ^{[1
]}

Gavrikova, Tatyana ^{[2
]}

Brown, Eric ^{[1
]}

Yamamoto, Masato ^{[1
]}

Vickers, Selwyn M. ^{[1
]}

Davydova, Julia ^{[1
]}

机构：

[1] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA

[2] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

来源：

AMERICAN JOURNAL OF SURGERY | 2012年 / 204卷 / 05期

关键词：

Pancreatic cancer; Oncolytic virus; Adenovirus; Conditionally replicative adenovirus (CRAd); Gene therapy; Interferon-alfa; Adenoviral death protein (ADP); Cox2; Krumdiek tissue slicer; ADJUVANT CHEMORADIATION THERAPY; ALPHA GENE-TRANSFER; SYSTEMIC IMMUNITY; VECTOR; PROMOTER; PANCREATICODUODENECTOMY; ADENOCARCINOMA; GEMCITABINE; SURVIVAL; ONYX-015;

D O I：

10.1016/j.amjsurg.2012.02.016

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

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. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：741 / 750

页数：10

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