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 anti-angiogenic 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. Many reports about endostar involved the treatment of non-small cell lung cancer, fewer reports are on 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 within stage IIB2 were selected, endostar combined with cisplatin+paclitaxel neoadjuvant chemotherapy (NACT) before radical 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 was used for statistical analysis of the study results. RESULTS: Endostar enhanced the 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 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 group exhibited obviously increase than NACT group. Tumor vascular maturation index α-SMA/CD31 in endostar group increased obviously than NACT group, correspondingly Ki67 staining for tumor proliferative rates, lymphovascular space invasion in endostar group further declined than NACT group. The genes and proteins expression of VEGFR2, Notch1, Notch4, Dll4, Jag1 were obviously downregulated in endostar group comparing to NACT group. CONCLUSION: Endostar restored vascular homeostasis in cervical cancer temporarily, enhanced chemotherapeutic agents effects in cervical cancer, increased patient OS ratio. Endostar+NACT treatment may provide a new target therapy for cervical cancer.