The Effect Of Low-Dose Metronomic Chemotherapy With Cisplatin On Tumor Angiogenesis Of H₂₂ Cell Growth Of Liver Carcinoma In Mouse Model

Objective To observe the efficacy of low-dose metronomic(LDM) chemotherapy with cisplatin for tumor angiogenesis on H₂₂ cell growth of liver carcinoma in mouse model,and investigate its anti-tumor effect and toxicity,in order to propose a new regimen of chemotherapy and provide theoretical evidence of its clinical application.Methods The H₂₂ cells of liver carcinoma were injected subcutaneously into KM mice. According therapy was randomly divided into four groups(n=12):LDM cisplatin therapeutic group A received intraperitoneal injection of cisplatin 0.6mg/(kg.d)every day and continually for five days in one week;LDM cisplatin therapeutic group B received intraperitoneal injection of cisplatin 1mg/(kg.d)every other day,and it was repeated three times in one week;maximum tolerated dose(MTD) cisplatin therapeutic group received intraperitoneal injection of cisplatin 9mg/(kg.d) once; control group received intraperitoneal injection of saline 0.2mL every day and continually for five days in one week.Then,we investigate change of tumorous volume,weight and toxicity.At the end of experiment,tumors were weighed after killed the mice.The histological characteristics of the tumor were performed by hematoxylin and eosin(HE) staining.The tumor microvessel density(MVD),the expression of vascular endothelial growth factor(VEGF),matrix metalloproteinase-2(MMP-2) and the proliferating cell nuclear antigen(PCNA) were detected by immunohistochemical staining.Resultsâ‘ In LDM cisplatin therapeutic group tumor continuously grew slow,while in MTD cisplatin therapeutic group tumor grew slowly at fast,then it accelerated on the 14th day of chemotherapy.Volumor and weight of tumors were much lower in mice received LDM cisplatin therapy than those in control group and MTD cisplatin therapeutic group at the end of experiment(F=59.30,68.49,q=4.08～19.01,P＜0.01).Side effect of chemotherapy:During the experiment, the body weight loss of mice were found in the mice received MTD cisplatin therapy.No obvious toxicity and apparent body weight loss were observed in LDM cisplatin therapeutic group.Necrosis increased significantly in the LDM cisplatin therapeutic group with few interstitial blood vessel.â‘¡The lever of MVD,the expression of VEGF and MMP-2 decreased significantly in the mice received LDM cisplatin therapy compared with those in control group and MTD cisplatin therapeutic group(F=9.56,9.38,10.17,q=3.56～6.18,P＜0.05),but they in MTD cisplatin therapeutic group were not significantly different from those in the control(q=1.36～2.27,P＞0.05).PCNA expression in LDM cisplatin therapeutic group decreased insignificantly compared with that in the control (F=11.95,q=0.87,P＞0.05),but it in MTD cisplatin therapeutic group was significantly different from it in the control and LDM cisplatin therapeutic group(q=6.10,6.17,P＜0.01).Conclusion Tumor growth and angiogenesis were inhibited significantly in the LDM cisplatin therapeutic group,which has better efficacy and lower toxicity than MTD cisplatin therapeutic group. The effect of anti-angiogenesis may be correlated with the decrease expression of VEGF and MMP-2 in the tumors.