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Bevacizumab (Bv) can be used synergistically with fluoropyrimidine‐based chemotherapy to treat colorectal cancer. 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‐fluorouracil (5‐FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti‐tumor effects of 5‐ FU  in LoVo colon cancer xenograft mice and increased the 5‐ FU  concentration in tumors without affecting hepatic 5‐ FU  metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase ( TP ) in tumors, which mediated the metabolic activation of 5‐ FU . Although  TP  is reported to promote angiogenesis and resistance, the combination of Bv and 5‐ FU  resulted in anti‐angiogenesis and vessel normalization in tumors, indicating that the elevated  TP  mainly contributed to the enhanced response to 5‐ FU . Bv also induced  TP  upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 ( VEGFR 2) antagonist apatinib and  VEGFR 2 silencing further confirmed  TP  upregulation. Bv and apatinib both enhanced the cytotoxicity of 5‐ FU  in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on  VEGFR 2 blockade and specificity protein 1 activation via  MDM 2 inhibition. In summary, Bv enhanced the accumulation of 5‐ FU  in tumors and the cytotoxicity of 5‐ FU  via  TP  upregulation. We provide data to better understand how Bv synergizes with 5‐ FU  from metabolic perspective, and it may give clues to the superiority of Bv in combination with fluoropyrimidine drugs compared to other chemotherapeutic drugs in colon cancer.

cancer science

Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway