Abstract
The adenomatous polyposis coli (APC) or β-catenin genes are frequently mutated in colorectal cancers, leading to activation of downstream genes with β-catenin/T-cell factor (Tcf)-responsive promoters. We have developed a gene therapy approach selectively targeting colorectal cancer cells in which β-catenin/Tcf4 pathway is activated by using a recombinant adenovirus AdTOP-CMV-TK, which carries a herpes simplex virus thymidine kinase gene (HSV TK) under the control of a β-catenin/Tcf-response promoter linking to a minimum CMV promoter. AdTOP-CMV-TK and ganciclovir (GCV) treatment significantly suppressed the growth of human DLD-1 colon cancer cells in nude mice. Furthermore, no significant tumor suppression effect was observed in human hepatoma cell line SK-HEP-1, in which the β-catenin/Tcf pathway is not activated, as a control experiment. In summary, we demonstrated the selective targeting of colorectal cancers with activated β-catenin by AdTOP-CMV-TK and GCV treatment in animal models, as well as its therapeutic potential for colon cancer metastasized to liver.
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Acknowledgements
We thank Dr Hans Clevers, (University Hospital, Utrecht, Netherlands) for generously providing TOP-fos-LUC (TOPFLASH), FOP-fos-LUC (FOPFLASH), TOPTK-LUC, and FOPTK-LUC plasmids. This work in part was supported by the Faculty Achievement Award (to M-C Hung) and the Breast Cancer Research Program of MD Anderson Cancer Center (to M-C Hung). KY Kwong–partial fulfilment of Ph.D. requirement for the Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston. C-P Day was a predoctoral fellow of the DOD/US Army Breast Cancer Training Grant No. DAMD17-99-9264.
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Kwong, K., Zou, Y., Day, CP. et al. The suppression of colon cancer cell growth in nude mice by targetingβ-catenin/TCF pathway. Oncogene 21, 8340–8346 (2002). https://doi.org/10.1038/sj.onc.1206050
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DOI: https://doi.org/10.1038/sj.onc.1206050
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