Endostar Rebuilding Vascular Homeostasis and Enhancing Chemotherapy Efficacy in Cervical Cancer Treatment

Background: The incidence rate of cervical cancer is the highest in the reproductive tract, and is not sensitive to chemotherapy. An appropriate amount of antiangiogenic agents can reconstruct tumor blood vessels in a short period of time and form vascular homeostasis, increase the function of blood vessel perfusion and reverse the multidrug resistance of chemotherapy, which is also called "vascular normalization".Endostar(a recombinant human endostatin) was developed by China and as a multi-target anti-angiogenesis agent.Endostar was mainly used in the treatment of non-small cell lung cancer,less reported in the treatment of cervical cancer. Purpose: To determine whether endostar can rebuild tumor vascular homeostasis and enhance chemotherapy effects for patients with cervical cancer. Methods: : In this study,the patients with cervical cancer were selected,endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy(NACT) before surgical operation was adopted, patients outcome and adverse reaction were followed up.The changes of tumor vascular structure and perfusion function before and after endostar given were evaluated by histopathology and dynamic contrast-enhanced magnetic resonance imaging(DEC-MRI). VEGF-Notch signal pathway was detected for the regulating mechanism of vascular proliferation in different groups. GraphPad Prism 6 software were used for statistical analysis of the study results. Results: : Endostar enhanced short-term (2 year) overall survival(OS) ,progression free survival(PFS) rates for cervical cancer patients.All the same,endostar increased long term (5 year) OS and PFS for cervical cancer patients.Endostar therapy exhibited with mild adverse reaction.MRI showed endostar+NACT further reduce tumor volume than NACT alone.The parameters of Ktrans,Ve for DEC-MRI in endostar groups exhibited obviously increase than NACT groups.Tumor vascular maturation index α-SMA/CD31 in endostar groups increased obviously than that of NACT groups, correspondingly tumor proliferative rate Ki67 staining in endostar groups further declined than NACT groups.The genes and proteins expression of VEGFR2,Notch1,Notch1,4,Dll4,Jagged-1 were obviously down regulated in endostar group comparing to that of NACT group. Conclusions: : Endorstar restored vascular homeostasis in cervical cancer temporarily, provided a new way to reverse chemotherapeutic agents resistance in cervical cancer, increased patient survival time.The VEGF-Notch connection was blocked by endostar playing a role in this effects.