Research On The Antitumor Effect Of Endostatin Associate With Chemotherapy And Discussion Of Its Mechanisms

Objective:To research the effects of Endostatin and Docetaxel on MMPs and the relationship between them to further investigate the mechanism of Endostatin.To investigate the changes of aCECs and Survivin after Endostar associate with chemotherapy and their significance to reflect therapeutic efficacy.Methods:After treatment with Endostatin,Docetaxel and in combination of them on xenograft tumor of A549 in mice,to detect markers as followings:Examine tumor tissue.Such as MMP-2,MMP-9,TIMP-1,TIMP-2 and EMMPRIN by immunohistochemistry;Detect active circulating endothelial cells in peripheral blood by flow cytometry.And we harvest NSCLC patients' peripheral blood,which are divided into four groups:Endostar associate with chemotherapy group(Endostar d1-14,chemotherapy d7-14);chemotherapy associate with Endostar group(Endostar d1-14,chemotherapyd1-7);operation group and chemotherapy group.And we detect pre- and post-therapeutically as followings:aCECs by flow cytometry;Survivin gene expression by real-time PCR;response to the therapy;Results:Endostatin,Docetaxel and in combination of them can statistically inhibit the growth of tumor(P=0.000;0.001;0.000);After treatment the express of MMP-2,MMP-9 and EMMPRIN are diminished in Endostatin group and combination group(P＜0.05);After treatment the expression of TIMP-1 and TIMP-2 are enhanced in Endostatin group and combination group(P＜0.05);The aCECs in peripheral blood are statistically increased in Endostatin group and combination group compared with model group.And aCECs are statistically increased in model group compared with control group.The amount of aCECs and expression of MMP-9 are negatively correlated(P=0.000);After seven days of Endostar's administration,aCECs are increased(P=0.035),which is different from chemotherapy group's downtrend;And the changes of the two groups are statistically different(P=0.041);Post-treatment,the profit patients of each group and operation group patients'aCECs expression have a downtrend;and the profit patients of Endostar associate with chemotherapy groups' Survivin also have a downtrend.Post-treatment,the advanced patients of each group' aCECs are raised up;and Endostar associate with chemotherapy advanced patients' Survivin are statistically increased(P=0.048),which is also statistically different from patients who post seven days administration of Endostar and who gained profit from Endostar associate with chemotherapy(P=0.000, 0.000);Post-treatment Endostar associate with chemotherapy advanced patients' aCECs and Survivin expression are statistically positively correlated(P=0.000). Conclusions:We proved that EMMPRIN is positively correlated with MMP-2 and MMP-9 in lung tumor tissue;Endostatin can inhibit tumor growth,diminish the expression of MMP-2,MMP-9 and EMMPRIN and enhance the expression of TIMP-1,TIMP-2.This prompts that Endostatin can inhibit tumor invision and depress capillary vessel permeability through effects on MMPs family;The aCECs in peripheral blood are increased,which demonstrates that Endostatin inhibites tumor growth through vascular normalization.According to this theory Endostatin should be administered before or along with chemotherapy drugs;Docetaxel and Endostatin have cooperation effects on each other;Post-treatment of Endostar aCECs are statistically increased.Trend of the changes of aCECs pre-and post-treatment are correlated with therapeutic effects;The expression of Survivin is correlated with therapeutic effects;Post-treatment in advanced patients Survivin is positively correlated with aCECs;aCECs and Survivin may be good markers to forecast therapeutic efficacy of anti-angiogenesis therapy of NSCLC patients;Up to now the RR and CBR in Endostar associate chemotherapy group,chemotherapy associate Endostar group and chemotherapy group are statistically no difference,and the TTP of each group is unavailable.