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Journal of Virology, June 2003, p. 6683-6691, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6683-6691.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Replicating Parvoviruses That Target Colon Cancer Cells

M. Malerba,1 L. Daeffler,2 J. Rommelaere,2 and R. D. Iggo1*

Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland,1 Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany2

Received 16 September 2002/ Accepted 18 March 2003

The wnt signaling pathway is constitutively activated in colon tumors by mutations in the adenomatous polyposis coli and ß-catenin genes. We have modified the minute virus of mice (MVM) P4 promoter to make it responsive to wnt signaling by inserting binding sites for the heterodimeric ß-catenin/Tcf transcription factor. In luciferase assays we can see up to 20-fold selectivity of Tcf mutant P4 promoters for cells with activated wnt signaling. Hybrid MVM/H-1 viruses containing Tcf mutant promoters were tested for NS1 expression, viral DNA replication, virus replication, and cytopathic effect on colon, lung, kidney, and cervical cancer cell lines. Activation of the wnt pathway by expression of {Delta}N-ß-catenin increased NS1 expression and viral burst size in 293T and H1299 lung cancer cells, showing that the Tcf mutant P4 promoter can respond to wnt signals in the context of the virus. Compared to the parental virus, the burst size of the Tcf mutant viruses was reduced at least 1,000-fold in H1299, 293T, NB324K, and HeLa cells, which have inactive wnt signaling pathways. The burst size and cytopathic effect of the Tcf viruses was near wild-type levels in SW480 and Isreco1 colon cancer cell lines, which have high Tcf activity. The high specificity of these viruses should permit the development of H-1 virus-based vectors which combine high safety and greater efficacy in cancer therapy.

* Corresponding author. Mailing address: ISREC, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41 21 692 5889. Fax: 41 21 652 6933. E-mail: richard.iggo{at}isrec.unil.ch.

Journal of Virology, June 2003, p. 6683-6691, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6683-6691.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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