Anticancer Activity of Oncolytic Adenovirus Vector Armed with IFN-alpha and ADP is Enhanced by Pharmacologically Controlled Expression of TRAIL

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2007 Nov 10

PMID 17992200

Citations 22

Authors

E V Shashkova

M N Kuppuswamy

W S M Wold

K Doronin

Affiliations

Soon will be listed here.

Abstract

We have previously described oncolytic adenovirus (Ad) vectors KD3 and KD3-interferon (IFN) that were rendered cancer-specific by mutations in the E1A region of Ad; these mutations abolish binding of E1A proteins to p300/CBP and pRB. The antitumor activity of the vectors was enhanced by overexpression of the Adenovirus Death Protein (ADP, E3-11.6K) and by replication-linked expression of IFN-alpha. We hypothesized that the anticancer efficacy of the KD3-IFN vector could be further improved by expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). E1-deleted Ad vectors were constructed carrying reporter genes for enhanced green fluorescent protein or secreted placental alkaline phosphatase (SEAP) and a therapeutic gene for TRAIL under control of the TetON system. Expression of the genes was increased in the presence of a helper virus and the inducer doxycycline such that up to 231-fold activation of expression for the TetON-SEAP vector was obtained. Coinfection with TetON-TRAIL augmented oncolytic activity of KD3 and KD3-IFN in vitro. Induction of TRAIL expression did not reduce the yield of progeny virus. Combination of TetON-TRAIL and KD3-IFN produced superior antitumor activity in vivo as compared with either vector alone demonstrating the efficacy of a four-pronged cancer gene therapy approach, which includes Ad oncolysis, ADP overexpression, IFN-alpha-mediated immunotherapy, and pharmacologically controlled TRAIL activity.

Citing Articles

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Sato-Dahlman M, Wirth K, Yamamoto M Cancers (Basel). 2018; 10(4).

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The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer.

Sato-Dahlman M, Yamamoto M Curr Cancer Drug Targets. 2017; 18(2):153-161.

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Oncolytic virus therapy for cancer.

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Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer.

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