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We have recently generated a CDX2 promoter\u2010controlled oncolytic adenovirus (Ad5\/3\u2010pCDX2) that showed an anticancer effect for CDX2\u2010positive upper gastrointestinal tumors. Here, we reported the anticancer effect of Ad5\/3\u2010pCDX2 for CDX2\u2010positive CRC and CRLM, and its combination efficacy with 5\u2010fluorouracil (5FU) in\u00a0vitro and in\u00a0vivo. We used HT29 as CDX2\u2010positive, and LS174T and SW480 as CDX2\u2010negative CRC cell lines. Without 5FU, Ad5\/3\u2010pCDX2 killed HT29 but not LS174T and SW480 cells. In\u00a0vitro, 5FU exposure upregulated CDX2 mRNA levels in all three cell lines. The 5FU combination enhanced the cytocidal effect and virus replication of Ad5\/3\u2010pCDX2 in CDX2\u2010negative LS174T. In mouse xenograft models, Ad5\/3\u2010pCDX2 monotherapy suppressed the HT29 subcutaneous tumor growth compared to the control group. The 5FU plus Ad5\/3\u2010pCDX2 combination therapy showed a remarkable antitumor effect over the efficacy of Ad5\/3\u2010pCDX2 monotherapy. In the LS174T subcutaneous tumor, although Ad5\/3\u2010pCDX2 monotherapy did not show an antitumor effect, the 5FU plus Ad5\/3\u2010pCDX2 combination therapy significantly suppressed the tumor growth compared to the Ad5\/3\u2010pCDX2 monotherapy. In mice with HT29 liver metastasis, intrasplenic injection of Ad5\/3\u2010pCDX2 induced virus replication in liver tumors and thus successfully attenuated tumor growth. In conclusion, Ad5\/3\u2010pCDX2 showed a significant anticancer effect that was enhanced by 5FU treatment in not only CDX2\u2010positive but also negative CRCs. Ad5\/3\u2010pCDX2 is a promising therapeutic modality for metastatic CRC such as CRLM.<\/jats:p>","DOI":"10.1111\/cas.70063","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T05:55:24Z","timestamp":1745560524000},"page":"1897-1907","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>CDX2<\/scp> Promoter\u2010Controlled Oncolytic Adenovirus Suppresses Tumor Growth and Liver Metastasis of Colorectal Cancer"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6516-9899","authenticated-orcid":false,"given":"Naohiko","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuho","family":"Sato\u2010Dahlman","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Minnesota  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