Mechanisms Of Improved Radiosensitivity By Recombinant Human Endostatin(Endostar) And Its Application In Clinical Practice

Part Ⅰ Effects of Endostar in combination with Radiotherapy on human Lung adenocarcinoma A549cells and its underlying mechanismsObjective:To explore the effect of Endostar on the biological behaviors such as proliferation, cell cycle, and apoptosis, and its underlying mechanisms.Methods:Conventional cell culture, and there were four groups:Control, Endostar(ES), radiotherapy(RT) and combination group. The MTT assay was used to measure the proliferation inhibitory rates, Hoechst assay was applied to detect the ratio of cellular apoptosis, ELISA and RT-PCR were introduced to test the expression of HIF-la, VEGF, bFGF, and TGF-β1.Results:Compared with Control group, ES was capable of inhibiting proliferation of A549cells in a dose dependent way, and the inhibitory rate at25ug/L was76.7%. The proportions of cells in cell cycle phase of G2/M and S were much higher than those in the Control group(P<0.05). When ES combined with RT, a significant apoptosis rate was achieved, compared to Control group and the other two groups(P<0.05). Further research revealed that the expression of HIF-la, VEGF, bFGF, and TGF-β1in combination group were obviously lower than those in the rest groups in dose-and time-dependent manner(P<0.05).Conclusions:ES has the ability of blocking proliferation and cell cycle in lung cancer, and the anti-tumor effect of radiotherapy was enhanced via inhibition of expression of HIF-la, VEGF, bFGF, and TGF-β1when combined with ES. Part Ⅱ Effects of En do star in combination with Radiotherapy on Mice with Lewis Lung Cancer and its underlying mechanismsObjective:To study the impact of Endostar in combination with radiotherapy on the growth and angiogenesis of tumor in mice with Lewis lung cancer.Methods:Four groups were included in this research:Control group, Endostar(ES) group, radiotherapy(RT) group and combination group. After treating mice with different interventions, the tumor growth curve was drawn based on daily measurement of tumor size and the inhibitory rate was calculated according to the weights of isolated tumors. Immunohistochemisty was used to detect the level of VEGF and microvessel density (MVD), and RT-PCT was applied to measure the relative expression of AQP-1and HIF-1α.Results:Compared with Control group, the growth rates, weight, and MVD of tumors in ES group, RT group and combination group were much lower (P<0.05). The expression of AQP-1and HIF-la was decreased when compared to Control and RT groups, however, there was no significant difference (P>0.05). A significant elevation in AQP-1associated with an obviously lower level of HIF-la was observed in combination group, and there was statistically significance when compared with the rest groups (P<0.05).Conclusions:ES in combination radiotherapy has a better performance of inhibiting growth and angiogenesis in lung cancer in-vivo than radiotherapy alone, and reduction of HIF-la and VEGF and up-regulation of AQP-1may be the potential underlying mechanisms. Part Ⅲ Endostar combined with concurrent chemoradiotherapy in treatment of locally advanced non-small cell lung cancerObjective:To evaluate the recent clinical efficacy and safety of recombinant human endostatin (Endostar, YH-16)combined with concurrent chemotherapy and radiotherapy in the treatment of locally advanced non-small cell lung cancer (NSCLC).Methods:The clinical datum of59patients confirmed by pathology with locally advanced NSCLC, were analyzed retrospectively. According to the inclusion criteria,30cases of them were treated by endostar plus chemoradiotherapy (trial group),29cases of them were treated by chemoradiotherapy(control group). The response rate(RR), clinical benefit rate(CBR),1-year overall survival rate and1-year progression free survival rate were evaluated for the short-term efficacy. The hematological toxicity, cardiactoxicity, gastrointestinal and radiation reactions were evaluated.Results:The response rates were66.7%and37.9%in trial group and control group respectively. The clinical benefit rates of the trial group and control group was respectively90%and69%. The difference of these two groups in RR and CBR were statistically significant (P<0.05). The1-year overall survival rate and1-year progression free survival rate in trial groupand control group were70.0%v,s53.3%and58.6%vs44.8%respectively without significant difference(P>0.05). The difference of main adverse reactions including hematological toxicity, cardiactoxicity, gastrointestinal and radiation reactions between the two groups were not statistically significant(P>0.05).Conclusions:Endostar combined with concurrent chemoradiotherapy can improve the short-term efficacy for advanced NSCLC and its toxicity can be tolerated.