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 demonstrated that the effect of Bv was dependent on VEGFR2 blockade and specificity protein 1 activation via MDM2 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.

Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

“…The blockage of new blood capillary formation reduces the supply of nutrients to tumors, and therefore inhibitor(s) of angiogenesis is able to strengthen the therapeutic effects of any anti-cancer drugs (e.g., 5-FU) [25,39]. Avastin is a recombinant and humanized monoclonal antibody, which is one of the most commonly-used anti-angiogenic drugs for cancer therapy, and works by binding with VEGF.…”

“…The efficacy of combined phytochemicals together with 5-FU on colon tumor growth was evaluated. Avastin, exerting an enhanced chemotherapeutic efficacy of 5-FU, served as a positive control [25]. The body weight of tumor-bearing mice was decreased after 5-FU treatment, and the weight reduction was restored in 5-FU-treated mice by application of Avastin, ginkgetin, resveratrol, or ginkgetin + resveratrol ( Supplementary Figures S3A and S5A, Figure 6A).…”

Experimental study of the vascular normalization window for tumors treated with apatinib and the efficacy of sequential chemotherapy with apatinib in lung cancer‐bearing mice and patients

“…At present, research on the normalization of antiangiogenic drugs has mainly focused on bevacizumab . Dickson used bevacizumab, an inhibitor of angiogenesis that neutralizes human VEGF, to examine vascular normalization in mice bearing human neuroblastoma xenografts.…”

Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

“…The efficiency of drug delivery in tumors is closely related to the structure and function of vessels 23 , 24 . For example, bevacizumab, an anti-angiogenic drug, enhances the effects of chemotherapy or radiotherapy by promoting the normalization of tumor vessels 25 , 26 , 27 . Since SMI has definite protective effect on cardiovascular system 2 , 11 , 12 , we inferred that SMI might increase chemotherapeutic drugs through regulating the blood vessels of tumors.…”