Experimental Study Of The Inhibiting Effect Of ALA-PDT Combined With 5-FU On Growth And Metastssis Of Gastric Cancer In Nude Mice

OBJECTIVES: To study the effects of PDT and/or 5-Fu on the growth and metastasis of gastric cancer in vivo.METHODS: Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. The mice were assigned into four groups at the fifth week after implantation. 5-Fu was administered ip at dose of 30 mg/kg every day till the mice were sacrificed. ALA was administered iv at dose of 100 mg/kg before the tumor-bearing mice were operated and the cancer lesion was irradiated by Helium-Neon laser bean. Output power density and energy density of laser light was respectively 150～200mW/cm2 and 135～180J/cm2. Three days and nine days after operation, tumor size and volume, inhibition rate, apoptotic index(AI), and the expression of Survivin,hypoxia inducible factor-1α(HIF-1α), vascular endothelial growth factor (VEGF) and micro vascular density (MVD) were evaluated respectively after the mice were sacrificed.RESULTS: Compared with control group at the first execution,the orthotopically implanted tumors were significantly reduced in weight [(2.34±0.12)g versus (2.02±0.42)g,(1.71±0.39)g and (1.33±0.04)g] in mice treated with 5-Fu, PDT and combined treatment with corresponding inhibition rate being 13.68%,26.92% and 43.16% respectively. The AI was increased significantly in the treated mice [(3.49±0.28) % versus (8.36±0.22)%,(18.52±0.17)% and (29.73±0.56)%]. The expression rate of Survivin was also decreased in turn in the treated mice [(0.272±0.075) versus (0.257±0.074),(0.128±0.061) and (0.109±0.053)]. The data show the significantly statistic difference(P<0.05). Stronger inhibitive effect on tumor was revealed in the combined group at the second execution yet. At the first execution, the expression rate of HIF-1αmRNA and protein was increased significantly in the mice of PDT group but decreased in that of combined group as compared with other groups [(0.722±0.108)%/(0.181±0.046) versus (0.655±0.080)%/(0.164±0.034), (0.926±0.128)%/(0.253±0.052) and (0.463±0.115)%/(0.076±0.017)] respectively. The VEGF production varied in accord with that of HIF-1αmRNA [0.114±0.037 versus 0.102±0.034,0.175±0.037 and 0.048±0.016]. The MVD was changed in the treated mice without prominent difference [28.34±7.11 versus 25.58±2.89,39.59±8.39 and 24.18±9.97].CONCLUSION:①5-Fu,ALA-PDT or combined treatment has strong inhibitory effect on tumor growth and proliferation of human gastric cancer implanted in nude mice and can raise the apoptosis index by inducing cell apoptosis in gastric cancer. ALA-PDT and 5-Fu can cooperate with each other on inducement of cell apoptosis by different way. ALA-PDT can still inhibit the expression rate of Survivin protein.②ALA-PDT can upregulate the expression of HIF-1αmRNA and protein significantly, accordingly result in higher expression of VEGF protein. But the expression of HIF-1αand VEGF in combined treatment group show declining trend significantly.③The combined treatment has hardly influence on the expression of MVD in tumor tissue on short terms.④The application of 5-Fu into ALA-PDT can improve the therapeutic effectiveness of PDT significantly, and reduce the side effect produced in course of administering PDT.