Fibroblast growth factor‐2 (FGF‐2) is one of the most important angiogenic factors to promote tumor growth, progression and metastasis. Neutralizing antibodies against FGF‐2 may suppress the growth of tumor cells by blocking the FGF‐2 signaling pathway. In this study, a disulfide‐stabilized diabody (ds‐Diabody) that specifically targets FGF‐2 was designed. Compared to its parent antibody, the introduction of disulphide bonds in the diabody could significantly increase the stability of ds‐Diabody and maintain its antigen binding activity. The ds‐Diabody against FGF‐2 could effectively inhibit the tube formation and migration of vascular endothelial cells and block the proliferation and invasion of human breast cancer cells. In the mouse model of breast cancer xenograft tumors, the ds‐Diabody against FGF‐2 could significantly inhibit the growth of tumor cells. Moreover, the densities of microvessels stained with CD31 and lymphatic vessels stained with LYVE1 in tumors showed a significant decrease following treatment with the ds‐Diabody against FGF‐2. Our data indicated that the ds‐Diabody against FGF‐2 could inhibit tumor angiogenesis, lymphangiogenesis and tumor growth.
Abstract. Bevacizumab has demonstrated a survival benefit in patients with metastatic colorectal cancer (mCRC) when combined with chemotherapy. Several randomized clinical trials comparing the efficacy and toxicity of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) against bevacizumab have been reported. The present meta-analysis was conducted to identify the potentially significant benefit of the combined treatment regimens in patients with mCRC. PubMed, Embase and Cochrane Library databases were searched for the randomized controlled trials published on or before September 2014, which compared the efficacy and toxicity of VEGFR TKIs with bevacizumab in combination with chemotherapy in patients with mCRC. The primary endpoints included progression-free survival (PFS), overall survival (OS) and overall response rate (ORR), and secondary endpoints were the toxicity profiles. Relative risks (RRs) with 95% confidence intervals (CIs) for response rate and adverse events (AEs) were calculated, as well as hazard ratios (HRs) for PFS and OS. The final analysis included 4 studies comprising a total of 1,929 intent-to-treat patients with mCRC, which compared VEGFR TKIs (cediranib and axitinib) plus chemotherapy with bevacizumab plus chemotherapy. Results demonstrated that VEGFR TKIs plus chemotherapy significantly resulted in a modest but significantly shorter PFS [hazard ratio (HR), 1.12; 95% CI, 1.00-1.25; P=0.05] compared with that of bevacizumab plus chemotherapy but not in OS (HR, 1.10; 95% CI, 0.88-1.17; P=0.87) and ORR (RR, 0.95; 95% CI, 0.85-1.05; P=0.30). VEGFR TKIs treatment showed a less favorable AE profile compared with bevacizumab, with higher rates of grade-III/IV diarrhea, fatigue, hypertension, neutropenia and thrombocytopenia, whereas a higher incidence of peripheral neuropathy associated with the bevacizumab group was observed. In conclusion, the addition of VEGFR TKIs to chemotherapy resulted in a modest but significantly shorter PFS but not in OS and ORR compared with bevacizumab. The VEGFR TKIs group showed a less favorable AE profile with higher rates of diarrhea, fatigue, hypertension, neutropenia and thrombocytopenia, whereas a higher incidence of peripheral neuropathy associated with the bevacizumab was observed.
Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are important proangiogenic factors in tumor procession. The autocrine and paracrine bFGF and the VEGF in tumor tissue can promote tumor angiogenesis, tumor growth, and metastasis. A VEGF/bFGF Complex Peptide (VBP3) was designed on the basis of epitope peptides from both VEGF and bFGF to elicit in vivo production of anti-bFGF and anti-VEGF antibodies. In this study, we reported on the production of recombinant VBP3 using high cell density fermentation. Fed-batch fermentation for recombinant VBP3 production was conducted, and the production procedure was optimized in a 10-L fermentor. The fraction of soluble VBP3 protein obtained reached 78% of total recombinant protein output under fed-batch fermentation. Purified recombinant VBP3 could inhibit tumor cell proliferation in vitro and stimulate C57BL/6 mice to produce high titer anti-VEGF and anti-bFGF antibodies in vivo. A melanoma-grafted mouse model and an immunohistochemistry assay showed that tumor growth and tumor angiogenesis were significantly inhibited in VBP3-vaccinated mice. These results demonstrated that soluble recombinant VBP3 could be produced by large-scale fermentation, and the product, with good immunogenicity, elicited production of high-titer anti-bFGF and anti-VEGF antibodies, which could be used as a therapeutic tumor vaccine to inhibit tumor angiogenesis and tumor growth.
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