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Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5\u2010fluorouracil (5\u2010FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti\u2010tumor effects of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> in LoVo colon cancer xenograft mice and increased the 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> concentration in tumors without affecting hepatic 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase (<jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content>) in tumors, which mediated the metabolic activation of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content>. Although <jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content> is reported to promote angiogenesis and resistance, the combination of Bv and 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> resulted in anti\u2010angiogenesis and vessel normalization in tumors, indicating that the elevated <jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content> mainly contributed to the enhanced response to 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content>. Bv also induced <jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content> upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 (<jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>2) antagonist apatinib and <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>2 silencing further confirmed <jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content> upregulation. Bv and apatinib both enhanced the cytotoxicity of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>2 blockade and specificity protein 1 activation via <jats:styled-content style=\"fixed-case\">MDM<\/jats:styled-content>2 inhibition. In summary, Bv enhanced the accumulation of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> in tumors and the\u00a0cytotoxicity of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> via <jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content> upregulation. We provide data to better understand how Bv synergizes with 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> from metabolic perspective, and it\u00a0may give clues to the superiority of Bv in combination with fluoropyrimidine drugs\u00a0compared to other chemotherapeutic drugs in colon cancer.<\/jats:p>","DOI":"10.1111\/cas.13779","type":"journal-article","created":{"date-parts":[[2018,8,29]],"date-time":"2018-08-29T22:29:12Z","timestamp":1535581752000},"page":"3294-3304","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Bevacizumab\u2010enhanced antitumor effect of 5\u2010fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A\/vascular endothelial growth factor receptor 2\u2010specificity protein 1 pathway"],"prefix":"10.1111","volume":"109","author":[{"given":"Wenyue","family":"Liu","sequence":"first","affiliation":[{"name":"State Key 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