Endostar inhibits ascites formation and prolongs survival in mouse models of malignant ascites

Abstract

Abstract. Endostar, a modified recombinant human endostatin, inhibits the growth of a variety of tumors by suppressing neovascularization. Vascular endothelial growth factor (VEGF) has an important role in malignant ascites formation. In order to determine whether Endostar can suppress the formation of ascites and prolong survival times, mouse models of malignant ascites were established using S180 and H22 tumor cells. The experimental mice were randomly divided into four groups: The three treatment groups received different doses of Endostar (4, 8 and 16 mg/kg), and the control group received 0.9% w/v NaCl. The volume of ascites, and the tumor cell, red blood cell (RBC), VEGF protein and mRNA content of the ascites was measured alongside the peritoneal permeability and the mouse survival time. In vitro analysis of cultured Endostar-treated S180 and H22 cells was also performed in order to examine cellular proliferation and the level of VEGF secreted protein and mRNA. The results revealed that Endostar suppressed the ascites volume, decreased the level of tumor cells, RBCs and VEGF in the ascites fluid, and lowered the permeability of the peritoneum. The tumor cells collected from the ascites in the Endostar-treated mice demonstrated a decrease in the expression of VEGF mRNA. The survival rates of the 8 and 16 mg/ kg Endostar-treated mice were longer than those of the controls. The in vitro experiments revealed a significant inhibition of VEGF protein secretion and VEGF mRNA by Endostar, but no effect on cellular proliferation. In conclusion, Endostar lowers ascites production by downregulating VEGF expression, and may therefore be effective for the treatment of malignant ascites. IntroductionMalignant ascites is caused by the accumulation of fluid in the peritoneal cavity following the intraperitoneal (i.p.) spread of tumor cells. Ascites can occur in a variety of cancers, including ovarian (37%), pancreaticobiliary (21%), gastric (18%), esophageal (4%), colorectal (4%) and breast (3%) cancer (1-3). Ascites may result in a poor quality of life due to symptoms of abdominal distention, pain, nausea, vomiting, anorexia, dyspnea, limb edema, insomnia and fatigue (1-3).Chemotherapy is a common first-line treatment for patients with ascites. However, limited evidence exists concerning its efficacy in patients with recurrent ascites. The i.p. administration of radioisotopes, or chemotherapy and peritoneovenous shunting procedures, has also been used (3,4). However, data regarding these approaches is also lacking. These methods are able to relieve the symptoms of recurrent ascites, but do not prolong survival (4). Repeated paracentesis is associated with regular hospital admissions and can lead to a number of problems, including pain, protein loss, hypovolemia, infection, peritonitis and bowel perforation (3,4). The preclinical and clinical evidence concerning anti-angiogenic agents, such as vascular endothelial growth factor (VEGF) antagonists and matrix metalloproteinase inhibitors, suggest that these agents may have...

Intraperitoneal Perfusion Therapy of Endostar Combined with Platinum Chemotherapy for Malignant Serous Effusions: A Meta-analysis

“…When combined with cisplatin, Endostar showed enhanced anti-cancer effect in esophageal cancer and lung cancer (Xu et al, 2014;Fan et al, 2015). Furthermore, Endostar inhibits ascites formation and prolongs survival in malignant ascites mouse models (Wei et al, 2015) and acquired 45%~100% effective rates in MSE patients when Endostar was admmonistrated through intraperitoneal perfusion combined with platinum (Yan et al, 2012). However, the related studies are single center RCTs with small sample size, and among each study, the treatment programs were confused and had no reference standard and consistent observation index.…”

Polysaccharides Extracted from Rhizoma Pleionis Have Antitumor Properties In Vitro and in an H22 Mouse Hepatoma Ascites Model In Vivo

“…Cells were then resuspended in saline at a concentration of 1 × 10 6 cells/mL. BALB/c mice received 0.2 mL of the cell suspension (5 × 10 5 cells per mouse) in the left peritoneal cavity, as previously described [ 45 , 46 ]. H22 tumor-bearing mice were randomly divided into five groups ( n = 16 per group): cyclophosphamide group, in which the mice were treated with cyclophosphamide (20 mg/kg), control group, in which the mice were given the same volume of physiological saline, and the PRP-treated groups, in which the mice were treated with 75, 150, or 300 mg/kg PRP.…”

The role of VEGF in the diagnosis and treatment of malignant pleural effusion in patients with non‑small cell lung cancer (Review)

“…The average progression-free survival (PFS) time for patients with MPE who received treatment with endostar in combination with cisplatin was 95 days, which was significantly longer than that of patients treated with cisplatin alone (PFS, 53 days; P=0.039) ( 57 ). Endostar has also been demonstrated to inhibit ascites formation and prolong survival in mouse models of malignant ascites established using S180 and H22 tumor cells ( 58 ). The tumor cells collected from the ascites in endostar-treated mice demonstrated a decrease in the expression of VEGF mRNA ( 58 ).…”

“…Endostar has also been demonstrated to inhibit ascites formation and prolong survival in mouse models of malignant ascites established using S180 and H22 tumor cells ( 58 ). The tumor cells collected from the ascites in endostar-treated mice demonstrated a decrease in the expression of VEGF mRNA ( 58 ). In addition, treatment of S180 and H22 tumor cells with endostar revealed a significant inhibition of VEGF protein secretion and VEGF mRNA expression, but no effect on cellular proliferation ( 58 ).…”

“…The tumor cells collected from the ascites in endostar-treated mice demonstrated a decrease in the expression of VEGF mRNA ( 58 ). In addition, treatment of S180 and H22 tumor cells with endostar revealed a significant inhibition of VEGF protein secretion and VEGF mRNA expression, but no effect on cellular proliferation ( 58 ). The inhibitory effects of recombinant human endostatin/endostar on tumor growth have also been reported in other cancer types, including ovarian cancer, malignant melanoma and colon cancer, and in liver transplantation-associated angiogenesis ( 59 ).…”