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
Abstract
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 (VEGFR2) antagonist apatinib and VEGFR2 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 demonstrat...Continue Reading
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Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy
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