Abstract:
Objective To observe and analyze the antitumor and anti-angiogenesis effects of rh-endostatin, to compare the effects of rh-endostatin on the microvasculature in tumor, myocardium, and renal tissue, and to investigate the underlying mechanism of endostar, the adverse effect of the cardiovascular system, for the purpose of directing its clinical application.
Methods Nude mice were randomized into four groups: blank control group(without tumor, NS 100μL·d-1), drug control group(mice without tumor, rh-endostatin 400μL·d-1), model group(mice with tumor, NS 100μL·d-1), and treatment group(mice with tumor, rh-endostatin 400μL·d-1).The drug was administered on days 1 to 28.The volume of the tumor and the weight of mice were measured before and after administration.QRT-PCR assay was conducted to detect the level of eNOS and nNOS mRNA in the tumor, myocardium, and kidney.The expressions of CD34, MMP-2, MMP-9, HIF-1α, VEGF, and iNOS in the tumor and kidney were detected through immunohistochemistry.The structure of vasculature was observed through immunoenzymatic double staining with CD34 and Masson.
Results 1) Resultsof the animal experiment: the tumor volume in the treatment group(75.60 mm3) was less than that in the model group(131.89 mm3).The discrepancy in weight was insignificant among the four groups.2)Resultsof the Real-time PCR: after treatment with endostar, the eNOS and nNOS mRNA levels in the mouse kidney significantly decreased.In the myocardium, the nNOS level significantly decreased.However, the eNOS level in the myocardium and the nNOS and eNOS levels in the tumor did not change significantly.3) After treatment with endostar, the expressions of MMP-9 and VEGF in the tumor were obviously downregulated.However, the same results were not found in the MMP-2 and HIF-1αof the tumor.MVD in the tumor of the treatment group significantly decreased compared with the model group.The proportion of tumor vessels covered by collagen in the treatment group increased compared with the model group.However, MVD and the microvasculature in the kidney did not change significantly.
Conclusion Rh-endostatin can reduce the expressions of MMP-9, VEGF, and MVD to inhibit the growth of tumor and to normalize the micrangium in the tumor.However, it cannot weaken the MMP and MVD of mature micrangium in the kidney.The eNOS and nNOS mRNA levels in the mouse kidney significantly decreased after treatment with endostar, which may be responsible for endostar causing hypertension.