The inhibitory effects of rh-endostatin (YH-16) in combination with radiotherapy on lung adenocarcinoma A549 in mice and the underlying mechanisms
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Endostatin
Objective:To investigate the wether vascular endothelial growth factor (VEGF) and endostatin could be used as new serum markers of endometriosis. Methods:Preoperative serum levels of VEGF and endostatin in 82 women with endometriosis(stage Ⅰ-Ⅱ 43 cases and stage Ⅲ-Ⅳ 39 cases) were assayed in duplicate using enzyme linked immunoadsordent assay. Serum levels were compared with levels of 60 healthy controls. Results: Serum VEGF and endostatin levels in endometriosis were significantly higher than that of controls. The levels of VEGF and endostatin of endonmetriosis stages Ⅰ-Ⅱ were significantly lower than those of stage Ⅲ-Ⅳ. The sensitivity, specificity, positive predictive value and negative predictive value of serum VEGF in detecting endometriosis were 0.92,0.78,0.82 and 0.90, respectively; those of enedostatin were 0.95, 0.84, 0.86 and 0.95, respectively. When both factors were used concomitantly, they were 0.98,0.75,0.76 and 0.98, respectively. Conclusion:These results indicates that the balance of angiogenic stimulators and inhibitors may regulate the development and progression of endometriosis and demonstrates that the circulating levels of both VEGF and endostatin maybe useful markers for endometriosis.
Endostatin
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Basic fibroblast growth factor (bFGF) was tested for its ability to stimulate angiogenesis in vivo using the rabbit corneal assay. Basic FGF (50-1,000 ng) was incorporated into 10% Hydron, and 50-500 ng of bFGF were incorporated into 10% Elvax. Human serum albumin (HSA) (10 ng) and 50 ng of transforming growth factor-beta (TGF-beta) served as negative and positive controls. Pellets of the polymers containing test compounds were implanted in the rabbit cornea, examined daily, and after 7 days corneal angiogenesis was scored on a graded scale [(-) for no response and +4 for a maximum response]. Histologic analysis of the corneas was performed on days 2 and 7. Basic FGF (50-500 ng) in Hydron failed to stimulate significant angiogenesis, though it did induce angiogenesis accompanied by inflammation at the 1,000-ng dose. Basic FGF in Elvax elicited inflammation-associated +3 to +4 responses at all doses tested. New blood vessels did not form in response to HSA in Hydron or Elvax, while TGF-beta induced +4 angiogenesis accompanied by vigorous inflammation. In vivo release kinetics for bFGF in Hydron and Elvax were compared, and the release of bioactive bFGF from Hydron and Elvax was demonstrated in vitro. These results suggest that the bFGF and Elvax combination incites an inflammatory response which stimulates indirect angiogenesis, while the same concentrations of bFGF delivered in Hydron produced no inflammation or angiogenesis. Although bFGF alone is a potent mitogen for endothelial cells, it does not appear to directly stimulate in vivo angiogenesis.
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Objective To investigate the effects of basic fibroblast growth factor (bFGF) small interfering RNA (siRNA) on the expression of vascular endothelial growth factor (VEGF) in pancreatic carcinoma cells.Methods The expression and secretion of VEGF and bFGF in pancreatic carcinoma cells were inhabited by VEGF siRNA and bFGF siRNA.The expression of VEGF in pancreatic carcinoma cells was detected by using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA).Results Both VEGF siRNA and bFGF siRNA significantly inhabited the expression of VEGF mRNA in Panc-1 and PCT-3 cells.Both VEGF siRNA and bFGF siRNA significantly inhabited the expression of VEGF in sw1990 and PCT-3 cells.Conclusion The bFGFsiRNA inhabited the expression of VEGF mRNA and VEGF in pancreatic carcinoma cells.
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Pancreatic carcinoma; Vascular endothelial growth factor; Basic fibroblast growth factor
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Objective: To observe the clinical effect and the influence of Thalidomide combined with chemotherapy on the level of plasma vascular endothelial growth factor(VEGF) and basic fibroblast growth factor(bFGF) in acute leukemia before and after treatment.Methods: 36 cases of acute leukemia patients were randomly divided into experimental group and control group,each 18 cases.Each group was treated with conventional chemotherapy in the standard-dose,meanwhile the experimental group was given Thalidomide 100 mg/d additionally.Before treatment and 8 weeks after treatment,plasma were collected for the detection of VEGF,bFGF content.Plasma VEGF and bFGF in 15 cases of healthy people were detected as the standard control value,compared with Leukemia patients.Results: The effective rate of experimental group and control group were 88.9%(16/18),77.8%(14/18) respectively,the difference was statistically significant(χ2=4.10,P0.05).The level of plasma VEGF and bFGF of experimental group and control group before and after treatment were[(389.78±249.94)ng/L,(211.74±36.72)ng/L],[(318.54±125.78)ng/L,(288.02±31.77)ng/L],[(2.43±0.27)μg/L,(2.09±0.17)μg/L],[(2.41±0.33)μg/L,(2.11±0.31)μg/L],the difference were significant compared with healthy group[(132.91±26.66)ng/L,(1.83±0.44)μg/L](P0.05);the level of plasma VEGF of experimental group after treatment was significantly different compared with control group(t=2.79,P0.05),but the level of plasma bFGF shows no difference between experimental group and control group(t=1.28,P0.05).Conclusion: Thalidomide combined with chemotherapy can improve the remission rate in patients with acute leukemia,and its mechanism may be conduced through inhibiting the plasma levels of VEGF and its receptor expression to active anti-proliferative,then take effect on anti-leukemia effection.
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Angiostatin
Endostatin
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4598 Endostatin, a 187 amino acid fragment from the C-terminus of collagen 18 has been shown to be a potent angiogenic inhibitor. Recently, it was demonstrated that p53 upregulates prolyl-4-hydoxylase, the enzyme responsible for cleaving endostatin from collagen 18. Because, endostatin has a very short half-life, we have expressed this protein fused to Fc. The half-life of endostatin is approximately 4 hours whereas it is approximately two weeks for Fc-endostatin, following injection in mice. This difference in half-life makes it possible to employ significantly smaller doses of Fc-endostatin. Previously, our laboratory established that the efficacy of endostatin in mice follows a U-shaped curve when examined as a function of the protein concentration. Anti-tumor activities of endostatin and Fc-endostatin were investigated. We now report that the amount required for inhibition of tumors by Fc-endostatin is at least 150-fold less than that of endostatin. This finding will likely have an impact on future trials of this inhibitor. Endostatin has been administered to patients in a Phase I and II clinical trials. Employing Fc-endostatin should enable us to generate sufficient protein for a more meaningful clinical trial of endostatin. Both Avastin (anti-VEGF monoclonal antibody produced by Genentech) and VEGF-trap ( Regeneron Pharmaceuticals ) employ similar Fc constructs for increasing the half-lives of their anti-angiogenic proteins.
Endostatin
Angiogenesis inhibitor
Fragment crystallizable region
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Angiogenesis plays an important role in physiological procedure and various tissue destructive pathological processes. It is thought that angiogenesis depends on a delicate balance between endogenous stimulators and inhibitors. Endostatin, as one of the important angiogenesis inhibitors, inhibits migration and tube formation of endothelial cells in vitro and angiogenesis in vivo. The mechanism of endostatin in inhibiting angiogenesis is complicated. It is demonstrated that endostatin inhibits proliferation, migration and tube formation of endothelial cells by interacting with VEGF, MMP-2 and integrin α5β1. Moreover, endostatin induces endothelial cells apoptosis by several pathways. This review describes the mechanism of endostatin in inhibiting angiogenesis and the role of endostatin in diseases related to angiogenesis.
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Endostatin, the proteolytic fragment of collagen XVIII, is an inhibitor of angiogenesis and tumor growth. Interestingly, elevated circulating endostatin levels have been found to correlate with poor patients' prognosis in several cancers. The aim of this study was to assess the prognostic value of endostatin in bladder cancer (BC) and to gain insight into the mechanisms involved in its production. This retrospective study included a total of 337 patients with BC and 103 controls. Collagen XVIII gene expression was analyzed using real-time PCR (n = 82). Endostatin tissue localization was assessed by immunohistochemistry (n = 27). Endostatin serum (n = 87) and urine (n = 153) levels were determined by ELISA. In 12 cases, both serum and paraffinized tissue samples from the same patients were available. We found decreased collagen XVIII tissue expression and increased endostatin urine and serum concentration in samples of patients with BC compared to controls. High serum endostatin levels correlated with the presence of lymph node metastases and MMP-7 concentrations and were independently associated with poor metastasis-free and disease-specific survival. Immunohistochemical analysis revealed a strong endostatin staining in the wall of tumor associated blood vessels in superficial but not in muscle-invasive BCs. Based on these, we concluded that elevated endostatin levels in patients with BC are the consequence of enhanced extracellular matrix degradation and are independent from collagen XVIII expression. Furthermore, serum endostatin levels may provide prognostic information independent from histopathological parameters and may therefore help to optimize therapy decisions. Loss of endostatin expression in tumor associated blood vessels might represent an important step supporting tumor-induced angiogenesis.
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Angiogenesis inhibitor
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To investigate the relationship of vascular endothelial growth factor (VEGF) and endostatin with endometriosis.The levels of vascular endothelial growth factor and endostatin were measured using ELISA in 50 women with endometriosis (stage I-II26 cases and stage III-IV 24 cases) in comparison with 42 women without endometriosis.The VEGF, endostatin concentrations and VEGF/endostatin ratio in endometriosis group were significantly higher than the mean value in the control group (P<0.01). The VEGF and endostatin levels in stages III and IV were both significantly higher than those in stages I and II(397+/-81 pg/ml vs 315+/-64 pg/ml, 125+/-62 ng/ml vs 66+/-40 ng/ml, P<0.01). However, the VEGF/endostatin ratio was lower in the advanced stages. There was no significant difference between follicular phase and luteal phase except that the VEGF level in follicular phase was higher than that in luteal phases.Both VEGF and endostatin may play a role in the regulation of angiogenesis of endometriosis, and the balance of angiogenic stimulators and inhibitors may be critical to the development of endometriosis.
Endostatin
Peritoneal fluid
Follicular fluid
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