Experimental Study On Anti-Angiogenic Effect Of Low-Dose Metronomic Chemotherapy With Cisplatin

Objective To study anti-angiogenic effect of low-dose metronomic chemotherapy with cisplatin in vitro and vivo.Methodsâ‘ We use MTT method to observe the influence of low-dose metronomic chemotherapy with cisplatin on HUVECs and HepG2 proliferation.â‘¡The H₂₂ cells of liver carcinoma were injected subcutaneously into KM mice.The mice accepted low-dose metronomic(LDM) chemotherapy with cisplatin(LDM:cisplatin 0.6mg/(kg.d)every day and continually for five days in one week) or maximum tolerated dose(MTD) chemotherapy with cisplatin(MTD:cisplatin 9mg/(kg.d) once).Then,We use immunohistochemical method to detected the expression of EGFR in tumors.â‘¢Chick embryo chorioallantoic membrane(CAM) model was used to check the inhibitory effect of low-dose metronomic chemotherapy with cisplatin on neovascularization in vivo:chick embryo were randomized into 5 groups(12 in every group) and incubated for 9 days.The CAM was treated with cisplatin by different doses for 3 days.The density of blood vessel of CAM was counted under microscope.Resultsâ‘ The continuous low-dose cisplatin(0.3～1.2μg/ml) could inhibit the prolifetation of HUVECs and the inhibited effect was dose-dependent and time-dependent(F=14.00～206.80, q=2.18～39.63,P＜0.05).Furthermore,experiments of inhibition of proliferation on HepG2 showed that low-dose cisplatin was ineffective(F=0.51～0.79,q=0.47～1.54,P＞0.05).â‘¡The expression of EGFR decreased significantly in the mice received LDM cisplatin therapy compared with those in control group and MTD cisplatin therapeutic group(F=140.67,q=4.17～22.31,P＜0.05).â‘¢The continuous low-dose cisplatin could suppress angiogenesis of CAM in vivo:Compared with physiological saline group,angiogenesis on CAM in low-dose cisplatin groups had heavy inhibition,accompanied by the decreased density of vessels(F=184.44,q=3.18～36.37,P＜0.05) with inhibitory rate of 30.87～60.61%.Conclusion Low-dose metronomic chemotherapy with cisplatin(non-cytotoxic concentration) has anti-angiogenic ability in vivo and in vitro.The effect of anti-angiogenesis may be correlated with the inhibition growth of the blood vessel endothelial cells and the decrease expression of EGFR.