| Purpose: The neovascularization is precondition of cancer growth and metastasis. Supressing angiogenesis is an effective method to inhibite the growth and metastasis of cancer. Nowadays,the inhibition of tumor angiogenesis has been a new targeted therapy for tumor. Angiotensin-converting enzyme inhibitor (ACEI) has been widely used as an antihypertensive agent. A retrospective cohort study of 5207 hypertension patients revealed that ACEI could decrease the incidence of adult cancer and fetal cancer. In vitro, ACEI retarded the growth of cultured cancer cells, inhibited the growth and angiogenesis of several tumors in various animal models. AngiotensinⅡis a multifunctional bioactive octapeptide of the renin-angiotensin system (RAS), acting not only as a vasoconstrictor but also as a growth promoter via angiotensinⅡtype 1 receptors (AT1). AT1 expresses in several tumor cells or tumor tissue. Candesartan is an angiotensinⅡtype 1 receptor antagonist. The present study made allograft models for hepatoma and gave the mice candesartan to determine whether AT1 antagonist could inhibit the development of hepatoma and suppress the tumor neovascularization. Method: To create the allograft models, H22 cells were injected into the subcutaneous tissue of right axil in BALB/c mice. Then the mice were randomizely devided into four groups:negtive control group (NEC),low dose candesartan group (LCA),high dose candesartan group (HCA) and flurouracil group (5-FU). Since twenty-four hours after tumors implanting, The four groups mice were respectively administered nomal saline,low dose candesartan (2.0mg/kg/d in body weight) and high dose candesartan (20mg/kg/d in body weight) by gavage once a day for 8 days. The flurouracil group mice were given flurouracil (25mg/kg in body weight) by abdominal injection once a day for 6 days. On day 9, the mice were sacrificed.All tumors were resected from mice,and total tumor weight in each mouse was measured. The mouse final weight,quality of life,tumor volume were also compared with each group. Subsequently, in order to evaluate the activity of AT1 antagonist for tumor angiogenesis, the expression of VEGF and CD34 in hepatoma were determined by immunohistochemical examination.Results: 1. With the growth of tumor, the mouse weight of NEC,LCA and HCA were gradually increased. However, the mouse weight of 5-FU group were decreased. The mouse mean final weight of each group was respectively 21.991±0.823,21.416±0.894,20.150±0.697 and 15.466±1.279. The mouse final weight in the group of NEC and LCA were significantly higher than in the group of HCA and 5-FU (P<0.05);The mouse final weight in the group of HCA were significantly higher than in the group of 5-FU (P<0.01);The mouse final weight in the group of NEC and LCA have no significant difference. 2. Compared with the group of NEC, the quality of life in the group of LCA,HCA and 5-FU was significantly improved, However, the group of LCA and 5-FU did not show obvious effect on improving the quality of life. 3. The mean tumor volume of each group was respectively 1504.35±564.99mm3,1119.96±358.57mm3,702.59±320.26mm3 and 669.17±200.77mm3. Compared with the tumor volume in group of NEC and LCA, the tumor volume in the group of HCA and 5-FU was significantly reduced (P<0.05);The tumor volume of LCA and NEC, HCA and 5-FU have no significant difficence. 4. The mean tumor weight of each group was respectively 1.455±0.416g,1.073±0.299g,0.743±0.231g and 0.719±0.289g. Compared with the tumor weight in the group of NEC, the tumor weight in the group of LCA,HCA and 5-FU were substantially reduced (P<0.01). Compared with the tumor weight in the group of LCA, the tumor weight in the group of HCA and 5-FU were significantly reduced (P<0.05);The tumor weight in the group of HCA and 5-FU have no obvious difficence. 5. The mean VEGF score of each group was respectively 6.091±1.221,5.083±1.240,4.083±1.165 and 5.917±0.900. The expression of VEGF in the group of LCA and HCA was significantly reduced compared with in the group of NEC (P<0.05);The expression of VEGF in the group of HCA was significantly reduced compared with in the group of LCA and 5-FU (P<0.05);The expression of VEGF in the group of NEC and 5-FU, LCA and 5-FU have no significant difficence. 6. The mean MVD of each group was respectively 24.773±2.573,20.300±3.577,17.150±2.713 and 23.592±2.866. The MVD of tumor tissue in the group of LCA and HCA was less than in the group of NEC and 5-FU (P<0.05);The MVD of tumor tissue in the group of HCA was less than in the group of LCA (P<0.05);The MVD in the group of NEC and 5-FU have no significant difference. 7. The mouse mean life time of each group was respectively 15.700±3.917,18.900±5.238,21.900±5.859 and 20.500±4.577. The mouse life time in the group of LCA,HCA and 5-FU was significantly prolonged compared with in the group of NEC (P<0.05);The mouse life time in the group of LCA,HCA and 5-FU have no significant diffirance.Conclusions: The results of the present study showed that selective AT1 antagonist candesartan can significantly inhibit the growth of the mouse allograft hepatoma, improve the quality of life, prolong the mouse life time, suppress the expression of VEGF in hepatoma, inhibit the tumor angiogenesis dose dependently. As a drug of tumor targeted therapy, AT1 antagonist could inhibit the tumor angiogenesis and play antitumor effect.
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