Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated effects of endostatin (ES) in the prometastatic microenvironment of inflammation occurring during the microvascular phase of cancer cell infiltration in the liver. We used a model of intrasplenic injection of B16 melanoma (B16M) cells leading to hepatic metastasis through vascular cell adhesion molecule-(VCAM-1)-mediated capillary arrest of cancer cells via interleukin-18 (IL-18)-dependent mechanism. We show that administration of 50 mg/kg recombinant human (rh) ES 30 min before B16M, plus repetition of same dose for 3 additional days decreased metastasis number by 60%. A single dose of rhES before B16M injection reduced hepatic microvascular retention of luciferase-transfected B16M by 40% and inhibited hepatic production of tumor necrosis factor alpha (TNF-alpha) and IL-18 and VCAM-1 expression by hepatic sinusoidal endothelia (HSE). Consistent with these data, rhES inhibited VCAM-1-dependent B16M cell adhesion to primary cultured HSE receiving B16M conditioned medium, and it abolished the HSE cell production of TNF-alpha and IL-18 induced by tumor-derived vascular endothelial cell growth factor (VEGF). rhES abrogated recombinant murine VEGF-induced tyrosine phosphorylation of KDR/flk-1 receptor in HSE cells, preventing the proinflammatory action of tumor-derived VEGF on HSE. rhES also abolished hepatic production of TNF-alpha, microvascular retention of luciferase-transfected B16M, and adhesion of B16M cells to isolated HSE cells, all of them induced in mice given 5 micro g/kg recombinant murine VEGF for 18 h. This capillary inflammation-deactivating capability constitutes a nonantiangiogenic antitumoral action of endostatin that decreases cancer cell arrest within liver microvasculature and prevents metastases promoted by proinflammatory cytokines induced by VEGF.
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PMID:Inhibition of cytokine-induced microvascular arrest of tumor cells by recombinant endostatin prevents experimental hepatic melanoma metastasis. 1472 38

Using a nonviral, electroporation-based gene transfection approach, we demonstrate the efficient and consistent transfection of two poorly immunogenic tumor cell lines: B16F10 melanoma and renal carcinoma (RENCA). Three genes, IL-12, angiostatin (AS), and an endostatin:angiostatin fusion protein (ES:AS) were subcloned into a DNA plasmid containing EBNA1-OriP, which was then transfected into B16F10 and RENCA cells. Significant levels of protein were secreted into the culture supernatants of transfected cells in vitro. Transfected tumor cells were injected subcutaneously into mice. All the three transgenes were capable of significantly delaying and reducing the formation of primary B16F10 and RENCA tumors, as well as B16F10 lung metastases. By day 11 post-injection, all control mice that received either mock-transfected or empty vector DNA-transfected B16F10 tumor cells had developed large primary tumors. In contrast, mice that received IL-12-transfected B16F10 cells did not develop appreciable tumors until day 17, and these were significantly smaller than controls. Similar results were observed for the RENCA model, in which only one of the IL-12 mice had developed tumors out to day 31. Expression of AS or ES:AS also significantly delayed and reduced primary tumors. Overall, ES:AS was more effective than AS alone. Furthermore, 25% of the AS mice and 33% of the ES:AS mice remained tumor-free at day 17, by which point all control mice had significant tumors. Mouse survival rates also correlated with the extent of tumor burden. Importantly, no lung metastases were detected in the lungs of mice that had received either AS or ES:AS-transfected B16F10 tumor cells and significantly fewer metastases were found in the IL-12 group. The consistency of our transfection results highlight the feasibility of directly electroporating tumor cells as a means to screen, identify, and validate in vivo potentially novel antiangiogenic and/or antineoplastic genes.
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PMID:Rapid, in vivo, evaluation of antiangiogenic and antineoplastic gene products by nonviral transfection of tumor cells. 1503 22

Transfection of the antiangiogenic angiostatin and endostatin genes was shown to be an alternative to high-dose administration of angiostatin or endostatin proteins for cancer therapy. We have systematically investigated whether coadministration of the mouse angiostatin kringle 1-3 gene (pFLAG-AngioK1/3) and the endostatin gene (pFLAG-Endo) complexed with cationic liposomes exhibits enhanced therapeutic efficacy. In vitro, the coexpressed mixture of angiostatin K1-3 and endostatin more effectively reduced angiogenesis in chorioallantoic membranes than either angiostatin K1-3 or endostatin alone. In vivo, subcutaneous co-administration of pFLAG-AngioK1/3 and pFLAG-Endo lipoplexes more effectively inhibited vascularization in Matrigel plugs implanted in mice than either one alone. Additionally, subcutaneous administration of these genes inhibited the growth and formation of pulmonary metastases of B16BL6 melanoma cells in mice. Compared to treatment with an empty vector, treatment with pFLAG-AngioK1/3 plus pFLAG-Endo inhibited 81% of tumor growth, while treatment with pFLAG-AngioK1/3 or pFLAG-Endo inhibited tumor growth 70 and 69%, respectively. Cotreatment with the two plasmids after primary tumor excision induced a 90% inhibition of pulmonary metastases versus 79% for pFLAG-AngioK1/3 or 80% for pFLAG-Endo individually. These results suggest that combined administration of angiostatin K1-3 and endostatin genes complexed with cationic liposomes may be an innovated antiangiogenic strategy for cancer therapy.
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PMID:Inhibition of B16BL6 tumor progression by coadministration of recombinant angiostatin K1-3 and endostatin genes with cationic liposomes. 1511 57

Endothelial cells involved in vasculogenesis and angiogenesis are key targets in cancer therapy. Recent evidence suggests that tumor cells can express some genes typically expressed by endothelial cells and form extracellular matrix-rich tubular networks, phenomena known as vasculogenic mimicry. We examined the effects of three angiogenesis inhibitors (i.e., anginex, TNP-470, and endostatin) on vasculogenic mimicry in human melanoma MUM-2B and C8161 cells and compared them with their effects in human endothelial HMEC-1 and HUVEC cells. Anginex, TNP-470, and endostatin markedly inhibited vascular cord and tube formation by HMEC-1 and HUVEC cells in vitro, whereas tubular network formation by MUM-2B and C8161 cells was relatively unaffected. Endothelial cells expressed higher mRNA and protein levels for two putative endostatin receptors, alpha5 integrin and heparin sulfate proteoglycan 2, than melanoma cells, suggesting a mechanistic basis for the differential response of the two cell types to angiogenesis inhibitors. These findings may contribute to the development of new antivascular therapeutic agents that target both angiogenesis and tumor cell vasculogenic mimicry.
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PMID:Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. 1546 37

The growth of tumor is angiogenesis-dependent and it often contains hypoxia and necrotic areas. Salmonella VNP20009 could target and replicate in hypoxia and necrotic areas within tumor and induce antitumor effect. Angiogenesis inhibitor endostatin could reduce tumor angiogenesis and inhibit its growth. However, in the phase I trials of VNP20009 and endostatin at the maximum-tolerated dose, no antitumor effects for bacteria therapy and minor therapeutic effects for endostatin treatment were seen. The ineffectiveness of these agents in clinical trials suggests that the combination of these agents with synergic modalities might be necessary. Here we described antitumor effects mediated by the combination of VNP20009 with recombinant human endostatin in B16F10 murine melanoma model with the aim to exploit tumor-targeting of bacteria and anti-angiogenesis strategy to enhance therapeutic efficacy. Combination therapy of these agents significantly enhanced antitumor effects by inducing greater tumor growth inhibition, more severe tumor tissue necrosis as well as less blood vessel density than those induced by either of treatments. The findings suggest that the combination of tumor-targeting bacteria with angiogenesis inhibitor might be of value for the treatment of solid tumors.
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PMID:Enhanced therapeutic effect by combination of tumor-targeting Salmonella and endostatin in murine melanoma model. 1612 82

In vivo expression of angiostatin and endostatin, two different types of endothelial cell growth inhibitor, have been reported to inhibit vascularization in tumor tissues, resulting in tumor growth inhibition. Recently, in vivo expression of saxatilin, a novel disintegrin purified from snake (Gloydius saxatilis) venom, was able to strongly inhibit endothelial cell proliferation and smooth muscle cell migration, resulting in tumor growth inhibition. However, the antitumor efficacy of the individual antiangiogenic molecules expressed in vivo was not sufficiently potent to induce tumor regression in animal models. Therefore, in this study, we have systemically examined how combinational transfer of angiostatin, endostatin, and saxatilin genes affects neovascularization in tumor tissues and tumor progression in a mouse model. In Matrigel-implanted mice, cotransfection with plasmids encoding angiostatin K1-3 (pFLAG-Angio K1/3), endostatin (pFLAG-Endo), and saxatilin (pFLAG-Sax) resulted in the most effective inhibition of angiogenesis. In addition, hydrodynamic cotransfection of the three genes induced more inhibition of B16BL6 melanoma growth and pulmonary metastasis than other combinations of transfected genes. Compared with the empty vector-treated control group, cotreatment with the three plasmids reduced B16BL6 tumor growth by 89% and pulmonary metastasis by 90%. These results provide additional evidence supporting the combined systemic expression of antiangiogenic factors, such as angiostatin K1-3, endostatin, and saxatilin, as an alternative procedure for antiangiogenic cancer therapy.
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PMID:Inhibition of angiogenesis and tumor progression by hydrodynamic cotransfection of angiostatin K1-3, endostatin, and saxatilin genes. 1641 Aug 25

Angiostatin and endostatin are potent endothelial cell growth inhibitors and have been carefully evaluated for antiangiogenic cancer therapy. Previously, we have shown that subcutaneous administration of angiostatin K1-3 and endostatin genes complexed with liposomal vectors is a more practical treatment procedure than administration of angiostatin and endostatin proteins. This study provides additional conclusive evidence supporting the effectiveness of antiangiogenic cancer gene therapy employing angiostatin K1-3 and endostatin genes. Plasmids encoding a mouse angiostatin K1-3 gene (pFLAG-AngioK1/3) and an endostatin gene (pFLAG-Endo) were introduced by the hydrodynamic transduction method into mice carrying Matrigel plugs or B16BL6 mouse melanoma tumors. A single systemic injection of the two genes exhibited potent antiangiogenic and antitumor activity in the mouse model. Hydrodynamic coadministration of the genes inhibited the B16BL6 mouse melanoma growth and pulmonary metastasis more effectively than administration of either gene alone. Compared with the untreated control group, the mice cotreated with pFLAG-AngioK1/3 and pFLAG-Endo exhibited 75% reduction of tumor growth while those treated with pFLAG-AngioK1/3 or pFLAG-Endo showed 46% and 52% reduction, respectively. The cotreatment inhibited B16BL6 pulmonary metastasis formation by 80% while the inhibition induced by individual treatment with pFLAG-AngioK1/3 or pFLAG-Endo was 68% and 71%, respectively. These results provide additional evidence that systemic expression of angiostatin K1-3 and/or endostatin genes is a viable alternative procedure for antiangiogenic cancer therapy.
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PMID:Antitumor effects of angiostatin K1-3 and endostatin genes coadministered by the hydrodynamics-based transfection method. 1649 52

Microencapsulation of recombinant cells is a novel promising approach to tumor therapy in which therapeutic protein is sustainable and long-term delivered by microencapsulated cells. The semi-permeable membrane of microcapsule can protect cell from host's immune rejection, increase the chemical stability of therapeutic protein and circumvent the problems of toxicity, limited half-lives and variation in circulating levels. Endostatin, a potent and specific angiogenesis inhibitor, could suppress the growth of primary and metastatic lesions in multiple murine tumor models. In this paper, APA microcapsules with high strength kept intact over 35 days and recombinant CHO cells kept the rapid proliferation viability and the continuous endostatin-expression function. The study of tumor treatment showed that the implantation of microencapsulated recombinant CHO cells decreased the neovascularization of tumor tissue by 59.4% and inhibited the B16 melanoma growth by 77.4%. Twenty days after tumor cell injection, 80% of animals treated with microencapsulated CHO-endo cells were alive compared to only 50% of animals in either control or mock control groups. Therefore, continuous delivery of endostatin from microencapsulated recombinant cells represents a feasible approach to tumor therapy.
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PMID:Tumor anti-angiogenic gene therapy with microencapsulated recombinant CHO cells. 1727 90

In patients with stage IIB-III disease, adjuvant high-dose interferon-alpha2b has shown clinical benefit, although metastatic melanoma is currently without any known survival-prolonging therapy. Angiogenesis has been considered important in melanoma progression, and endostatin is an angiogenesis inhibitor with antitumor activity that has shown promising results in murine model systems, prompting investigation of a formulation of rh-Endostatin (EntreMed, Rockville, Maryland, USA) alone and with interferon in metastatic melanoma. Patients were randomly assigned to receive interferon alpha2b (Schering-Plough) 10 million units/m(2) subcutaneously three times a week plus rh-Endostatin 45 mg/m(2) subcutaneously every 12 h (arm A) vs. rh-Endostatin alone (arm B). Twenty-one patients (age range 31-77 years, median age 54, 12 men and nine women, 17 cutaneous, and four ocular melanomas) were enrolled. No antitumor responses were observed, and no significant differences were noted in time to progression or overall survival. Two patients had stable disease enduring more than 30 weeks on treatment. Serum endostatin levels increased significantly 4 weeks after treatment in both groups. Basic fibroblast growth factor levels in urine were significantly lower following treatment in patients on arm B (P=0.043). The percentage of circulating endothelial cells was increased in five evaluable patients 4 weeks after treatment. Low titer (<or=1:25) IgG antibodies against the rh-Endo formulation were detected in two patients (one per arm) in cycle 4. In conclusion, interferon did not improve response rate of rh-Endo although prolonged disease stability was observed in two patients. Better laboratory correlates of antiangiogenic response are needed, and the predictive value of circulating endothelial cells warrants further evaluation.
Melanoma Res 2007 Jun
PMID:Endostatin plus interferon-alpha2b therapy for metastatic melanoma: a novel combination of antiangiogenic and immunomodulatory agents. 1750 65

Microencapsulation of recombinant cells is a novel alternative approach to tumor gene therapy. Therapeutic protein delivery can be sustained for systemic treatment of tumors because the recombinant cells are enclosed in microcapsules and the semipermeable membrane of the microcapsules protects the cells from host immune rejection and reduces the need for frequent injection. In this study, we describe a method to systemically inhibit tumor growth by in vivo culture of antiangiogenic endostatin-secreting Chinese hamster ovary (CHO) cells in microcapsules as small as 200 microm in diameter. Peritoneal administration of encapsulated endostatin-CHO cells inhibited melanoma growth to 66.4% and enhanced the survival of treated mice to 80% by 27 days posttreatment. Continuous systemic release of endostatin from microcapsules offers an effective therapeutic strategy to eradicate solid tumors.
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PMID:In vivo culture of encapsulated endostatin-secreting Chinese hamster ovary cells for systemic tumor inhibition. 1751 15


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