| Studies have proved that angiogenesis is a critical pathological process for the development and metastasis of solid tumor. What's more, the disorganized and leaky vessels in tumor can contribute to chemotherapy. Theoretically, selectively blocking some step in the angiogenic process or some critical pro-angiogenic factors is a rational strategy to inhibit tumor growth and metastasis, and cure cancer.VEGF-VEGFR pathway is known as the most important information signal for vascularization. So, inhibiting this pathway by targeted method has become prevailing in tumor therapy study. According to this theory, many agents have been created to treat tumor, (1) the antibody binding VEGF directly (such as Avastin), (2) the antibody inhibiting VEGFR (such as DC 101), (3) the inhibitor of tyrosine kinase receptor (such as Sunitinib), (4) VEGF decoy (such as VEGF-trap)…and all these drugs have performed some effect. One of these, FDA approved Avastin, was successfully used in clinic, performed definite efficacy, and proved the theory is right, which bought us a new idea to treat malignant tumor.VEGF-Trap, is a VEGF decoy which contains the extracellular domain 2 of vascular endothelial growth factor receptor 1(VEGFR1, Flt-1) and extracellular domain 3 of VEGFR2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Finished vitro tests and clinic trails have showed the expected efficacy, and it is now tested in phase III trial.FP3/KH902 is novel antiangiogenesis drug with independent intellectual property rights in our country. And whose structure is similar to VEGF-Trap, which contains the extracellular domain 2 of vascular endothelial growth factor receptor 1(VEGFR1, Flt-1) and extracellular domain 3,4 of VEGFR2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin Gl. Previous studies indicated that it could efficiently bind VEGF. In the present study, we manage to study the therapeutic effect of FP3 in treatment of colorectal cancer (CRC) via cell line assay in vitro and nude mice xenografts test in vivo, and try to clue its mechanism.The contents are listed below:Study in vitro:MTT assay was performed to evaluate the influence of human umbilical vein endothelial cells (HUVECs) on the proliferation. The wound healing test was used to examine the migration ability change of HUVECs caused by FP3, Aortic ring assay was performed to test the effect of FP3 to VEGF-induced vessel sprouting.Study in vivo:Node mice tumor xenografts with HT29 cell line and CRC patient derived tumor were established to test the antitumor efficacy of FP3 and its potential mechanism. During the treatment, we measured the volume of xenografts periodically to verify the effect of FP3 on these tumors; weigh the weight of xenografts to learn the adverse reaction. After the treatment, immunohistochemistry (IHC) was applied to analyze the effect of FP3 on microvessel density (MVD) and the cell proliferation in the xenografts.Results revealed:In vitro, FP3 can significantly inhibit the proliferation and migration of HUVECs, and VEGF-induced aortic ring sprouting was significantly suppressed by FP3. However, FP3 didn't show any inhibit effect on HT29, HCT116, SW620 Etc. CRC cell lines. In vivo, the growth of FP3 treated HT29 xenografts and CRC patient derived tumor xenografts is slower than the control group, lower MVD and slower cell proliferation were watched in FP3 treated xenograft tumor. These suggested that FP3 can suppress CRC xenografts growth by reduce MVD and inhibit the proliferation of tumor cell in CRC xenografts, but not reduce the production of VEGF in xenografts.Conclusion:Cell line study in vitro and xenograft mode study in vivo revealed that, the novel antiangiogenic agent FP3 can act just like Avastin in the treatment of CRC, and the potential mechanism is inhibiting the angiogenic activities.
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