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Journal of Virology, March 2001, p. 2857-2865, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2857-2865.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Replicating Adenoviruses That Target Tumors with Constitutive Activation of the wnt Signaling Pathway

Michele Brunori, Maddalena Malerba, Haruhiko Kashiwazaki,dagger and Richard Iggo*

Swiss Institute for Experimental Cancer Research (ISREC), 1066 Epalinges, Switzerland

Received 11 October 2000/Accepted 24 December 2000

Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which rationally target known causal oncogenic defects. Selectively replicating viruses have a major advantage over nonreplicating viruses to target these defects because the therapeutic effect of the injected virus is augmented by virus produced within the tumor. To permit rational targeting of colon tumors, we have developed replicating adenoviruses that express the viral E1B and E2 genes from promoters controlled by the Tcf4 transcription factor. Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and beta -catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue. The Tcf-E2 and Tcf-E1B promoters are active in many, but not all, cell lines with activation of the wnt pathway. Viruses with Tcf regulation of E2 expression replicate normally in SW480 colon cancer cells but show a 50- to 100-fold decrease in replication in H1299 lung cancer cells and WI38 normal fibroblasts. Activation of wnt signaling by transduction of a stable beta -catenin mutant into normal fibroblasts renders the cells permissive for virus replication. Insertion of Tcf4 sites in the E1B promoter has only small effects on replication in vitro but significantly reduces the inflammatory response in a rodent lung model in vivo. Replicating adenoviruses with Tcf regulation of both E1B and E2 transcription are potentially useful for the treatment of liver metastases from colorectal tumors, but additional changes will be required to produce a virus that can be used to treat all colon tumors.

* Corresponding author. Mailing address: Swiss Institute for Experimental Cancer Research (ISREC), Boveresses 155, 1066 Epalinges, Switzerland. Phone: 41 21 692 5889. Fax: 41 21 652 6933. E-mail: Richard.Iggo{at}isrec.unil.ch.

dagger Present address: Section of Oral & Maxillofacial Surgery, Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo City, Hokkaido 060-8586, Japan.

Journal of Virology, March 2001, p. 2857-2865, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2857-2865.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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