Evaluation Of DCE-MRI Of The Response Of Pulmonary Carcinoma Xenografts In SCID Mice To The Neovessels-Targeting Tie2 Agent

BackgroundAngiogenesis plays a pivotal role in the development, growth, and metastasis of malignant tumors, and inhibiting tumor angiogenesis can significantly supress tumor growth and metastasis. In recent years, tumor angiogenesis has become a new target for anti-cancer drugs. Ang/Tie2 system including angiopoietin (angiopoietin, Ang) and its receptor Tie2 (tyrosine kinase with Ig and EGF ho2mology domains), is one signal transduction pathway in addition to vascular endothelial growth factor in angiogenesis, this signal pathway plays an important role in the process of angiogenesis in embryonic and adult stages. Therefore, the research on Ang/Tie2 system will help clarify the mechanism of angiogenesis, and these targets could be useful for the tumors anti-angiogenesis gene targeted therapy. Now there are many reports for the Tie2 receptor to inhibit tumor angiogenesis, and some studies reported they had used Tie2 inhibitor-ExTeK·6His in the therapy, and tumor volume reduced by 75% after 10d. This anti-angiogenesis therapy may be a new way, and we need adopt a precise means to monitor and evaluate treatment effect in tumor angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (dynamic contrast-enhanced MRI, DCE-MRI) is a functional imaging method. It can non-invasively evaluate the structure and functional properties of tumor vascular by tracking the pharmacokinetics of contrast agent through the blood vessels by iv. As a relatively new imaging technique, DCE-MRI can show the capillary structure and vascular permeability, vascular blood volume and blood flow changes inside and outside. It have been widely used to monitor tumor angiogenesis and evaluate the efficacy of antitumor drugs. In our study, first of all we assessed the feasibility of DCE-MRI and optimized the scanning condition, and then evaluate the effect of soluble Tie2 antibody against lung cancer xenograft in SCID mice using DCE-MRI.Part One The Study of DCE-MRI Monitoring the Neovessels of the High and Low Metastatic Pulmonary Carcinoma Xenografts in SCID MiceObject To explore the feasibility of DCE-MRI-monitoring the neovessels of the high and low metastic pulmonary carcinoma xenografts in SCID mice.Methods The 24 SCID mice were assigned randomly to A or B groups. A group is low metastic pulmonary carcinoma, and B group is high metastic pulmonary carcinoma; NCI-H460 cells (A group) and Murine Lewis lung carcinoma (LLC) cells (B group) were subcutaneously implanted into the dorsal midline of for murine tumors respectly, the cells were in logarithmic phase and cell concentration was 1×107mol/l. After 7-10 days, when the volume of xenografts grew to about 1cm3,all mice underwent scanning on the same 3 Tesla MRI system. Each scanning session consisted of the following sequences:T2-weighted images、T1 images and Dynamic contrast-enhanced images,and we got four kinetic parameters:Ktrans、kep、VeiAUC, which indicated the neovessels of tumor. After last MR examinations, tumors were harvested, fixed in formalin, and paraffinembedded sections were stained for CD31.Compared the immunohistochemical image with the results of DCE-MRI at last.Results Compared with A (low metastic) group, the four kinetic parameters of B (high metastic) group were higher; In Nonparametric Test,Ktrans、kep and iAUC all showed significant difference(P<0.05), and Ve showed no significant difference between two groups(P>0.05). The immunohistochemical image showed the blood vessels of low metastic pulmonary carcinoma more sparse,which was according with the results of DCE-MRI.Conclusion Compared high metastic tumor with low metastic tumor, tumor vascular permeability and perfusion were higher; the scan protocol and hemodynamic model of DCE-MRI was feasiblePart Two Evaluation of DCE-MRI of the Response of Pulmonary Carcinoma Xenografts in SCID Mice to the Neovessels-Targeting Tie2 AgentObject To assess the effect of different Tie2 Agent over expression on the structure of the tumor vasculature and the proliferation of the cancer cells using quantitatively characterizing tumor neovessels by MRI Methods The 18 SCDD mice were randomly divided into three groups; Murine Lewis lung carcinoma (LLC) cells were subcutaneously transplanted into the dorsal midline of SCID mice for murine tumors, and 109 pfu of Tie2 Agent adenoviruses、the control adenovirus AdLacZ、Ang1 Agent adenoviruses were given respectly by i.v. tail-vein injection next day; then all animal underwent scanning on the same 3 Tesla MRI system. MR examinations were performed after 8 days and 17 days after drug-treatment. After last MR examinations, tumors were harvested, fixed in formalin, and paraffinembedded sections were stained for CD31. Then compared the immuno-histochemical image with the results of DCE-MRI.Results 8 days after animal inoculation, the four vascular function parameters of AdExTeK group were lower than AdLacZ group,and the difference was significant, then Ktrans、kep.、Ve and iAUC in AdAngl group all were higher, the difference was also significant(P<0.05); 2 weeks later, the four vascular function parameters of AdExTeK group were lower than AdLacZ group, and the difference was significant(P<0.05). The three groups had no significant difference in tumor volume. The immunohistochemical image of AdExTeK group showed more sparse vessels than AdLacZ group, which was according with the results of DCE-MRI.Conclusion Soluble Tie2 antibody has inhibitory effect against the neovessels of pulmonary carcinoma in mice by blocking a new signal pathway of angiopoiesis in addition to VEGF—Ang1/Tie2 system.