| Objective: The gastric carcinoma is the malignant tumor, which seriously endanger mankind's health and life. The incidence of gastric carcinoma ranks second of malignant tumors. Surgical operation is the first therapy of gastric carcinoma, however, most patients lost the opportunity of surgery when they were clearly diagnosed. The recurrence rates remain as high as 80% after tumor resection. So chemotherapy is the conventional treatment of the metastatic gastric carcinoma or tumor which can not been resected. People do not find received"gold standard"chemotherapy for the advanced gastric carcinoma at present. The conventional chemotherapy used in gastric carcinoma remains unsatisfactory for the rates of cure and survival. Numerous studies have shown that tumor growth is dependent on angiogenesis, thus providing a rationale for antiangiogenic therapy. Targeting tumor vasculature has been a new therapeutic strategy. Endostatin, compared with conventional chemotherapy, possesses low toxicity, broad -spectrum of action and absence of drug resistance. Of the known angiogenesis inhibitors, endostatin is the most potent inhibitor of tumor angiogenesis. In vitro studies have shown that endostatin specifically inhibits endothelial proliferation without a direct effect on tumor cells growth. Endostatin inhibits tumor growth, with reduction of virtually all tumor neovascularization and without detectable systemic toxicity in preclinical models.Emerging data suggest that anti-angiogenesis alone may be limited in advanced tumors. In recent years there has been an increasing interest in attempting to combine chemotherapy with angiogenesis inhibitors for tumor suppression. Combination therapy with endostatin and chemotherapeutic drugs showed a stronger effect in mammary carcinoma, hepatic cancer and lung cancer models. A novel recombinant human endostatin (endostar), combined with NP chemotherapy studied by scholars of our country, was approved by the State Food and Drug Administration of China in 2005 for the treatment of non-small- cell lung cancer. Oxaliplatin is a third generation platinum compound. Similarly to other platinum compounds, the main mechanism of oxaliplatin is mediated through the formation of DNA-adducts. Since Pt-DNA adducts are capable of blocking both DNA replication and transcription, they are considered the major cytotoxic lesions. Oxaliplatin is applied clinically against several solid tumors, such as colorectal carcinoma, esophageal cancer, gastric cancer and ovarian cancer, et al.In this study, we establish stomach carcinoma model to investigate the anti-tumor effects and mechanism of the recombinant human endostatin combined with oxaliplatin on gastric carcinoma for providing experimental evidence for further clinical application.Methods: Forty healthy C57 mice were used to establish stomach carcinoma model by subcutaneously injection of 2×106/0.2ml mouse fore stomach carcinoma cells into the flank. Forty tumor-bearing mice were randomly divided into control group, endostar-treated group, oxaliplatin-treated group and combination treated group. The number of mice in each group is 10. The control group was given saline ip. injection. Endostar treated group was given endostar 0.8mg/kg d1-14, ip. The oxaliplatin-treated group was given 5mg/kg, d1, ip. The combination treated group was given endostar and oxaliplatin. We observe the daily general and measure tumor volume every two days. We measure tumor weight and volume, calculate tumor inhibition rate and draw tumor growth curve after the mice being killed a week later. The cell apoptosis of tumor tissue was analyzed by flow cytometry. Expression of Bcl-2, Bax protein and microvessel density in tumor tissue was detected by immunohistochemical staining. The results of the statistical analyses are presented as mean values±standard deviation (SD). Differences between the groups were tested by performing ANOVA(SNK). All p values were two-sided and statistical significance was defined as p<0.05.Results: 1 The tumor weights and inhibiting rates: The tumor weight of each group is 1.778±0.119g, 0.822±0.107g, 0.506±0.097g, 0.30±0.066g, respectively. There were signify- cant differences among all groups (P<0.05). Inhibiting rate of treated groups is 53.77%, 71.54%, 83.13%, respectively.2 Changes of tumor volume: The tumor volume increased gradually in control group, and reached 1211.15±70.71mm3 at 22nd day. Tumor volume of treated groups increases slowly compared with the tumor volume of control group. The tumor volume did not increase obviously in endostar-treated group; the volume was 293.02±53.49mm3 at 22nd day. Tumor volume of oxaliplatin-treated group gradually decreased after 10 days, and which of combined treated group decreased a week later. It was 141.72±44.92mm3 and 63.90±35.28mm3 at 22nd day. The tumor volume in combined group dropped most. There were significant differences among all groups (P<0.05).3 Apoptosis of rate: Apoptosis of rate of each group is 17.38±1.58%, 26.79±3.12%, 29.61±3.09%, 37.92±2.78%, respectively. There was significant difference between the control group and treated groups (P<0.05). Apoptosis of rate in combined group was the highest, compared with endostar- treated group or oxaliplatin-treated group (P<0.05).4 The expression of Bcl-2 and Bax: The expression of Bcl-2 protein in each was group 57.60±6.11%, 31.0±5.35%, 20.1±3.67%, 3.41±3.0%, respectively. There was a significant difference among each group (P<0.05). The expression of Bax protein in each group was 19.2±4.18%, 21.1±4.23%, 41.7±7.65%, 45.9±7.91%, respectively. There was no statistically significant difference between control and endostar-treated group, oxaliplatin-treated and combined treated group (P>0.05). There was statistically significant difference between the control, endostar-treated group and oxaliplatin-treated, combined treated group (P<0.05).5 The effects of treatment on vascular growth: The expression of CD34 in each group was 4.11±0.86, 2.29±0.63, 3.38±0.91, 1.60±0.61, respectively. The microvessel density of tumors in the endostar treatment group was significantly less than that of the control group (p<0.05). The microvessel density of tumors in the combination treatment group was significantly less than that of the endostar or oxaliplatin treatment group (p<0.05). Conclusions: 1 Endostar combined with Oxaliplatin could inhibit the proliferation of stomach carcinoma cells.2 Endostar combined with Oxaliplatin could inhibit the angiogenesis of tumor.3 Endostar combined with Oxaliplatin could increase the apoptosis of tumor cells, down-regulate the expression of Bcl-2 and up-regulate the expression of Bax. The possible mechanism of inducing cells apoptosis is related to decrease the rate of Bcl-2/Bax.
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