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Angiogenesis Inhibitor (angiogenesi + inhibitor)
Selected AbstractsTriptolide functions as a potent angiogenesis inhibitorINTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Ming-Fang He Abstract Triptolide is a key anti-inflammatory compound of the Chinese herbal medicine Tripterygium wilfordii Hook. f. (Celastraceae). It also possesses potent antitumor activity. In this study, we show that triptolide is an angiogenesis inhibitor based on various angiogenesis assays. The IC50 in in vitro assays was 45 nM, which was much lower than the plasma concentrations of triptolide in the rat or human administered with T. wilfordii extracts for treating inflammation. When dosed in vivo, triptolide potently inhibited angiogenesis at 100 nM in Matrigel plug assay. Triptolide at 0.75 mg/kg/day significantly blocked tumor angiogenesis and tumor progression in murine tumorigenesis assay. The underlying mechanism of triptolide correlated with downregulation of proangiogenic Tie2 and VEGFR-2 expression in human umbilical vein endothelial cell by semiquantitative RT-PCR and western blot analysis. Although Tie2 inhibition appeared to be a later event as compared with VEGFR-2, Tie2 overexpression significantly attenuated the inhibitory effect of triptolide on endothelial proliferation and network formation. By contrast, Tie2 knockdown mimicked the inhibitory effect of triptolide on endothelial network formation. Our findings suggest that antitumor action of triptolide is partly via inhibition of tumor angiogenesis by blocking 2 endothelial receptor-mediated signaling pathways, and triptolide can be a promising antiangiogenic agent. [source] Angiogenic activity of multiple myeloma endothelial cells in vivo in the chick embryo chorioallantoic membrane assay is associated to a down-regulation in the expression of endogenous endostatinJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2008Domenica Mangieri Abstract We have attempted a fine characterization of the angiogenic response induced by multiple myeloma endothelial cells (MMEC) by using the chick embryo chorioallantoic membrane (CAM) assay and by reverse transcriptase-polymerase chain reaction (RT-PCR). Results showed that in the CAM assay MMEC induced an angiogenic response comparable to that of a well-known angiogenic cytokine, namely fibroblast growth factor-2 (FGF-2), while RT-PCR demonstrated that the expression of endostatin mRNA detected in MM treated CAM was significantly lower respect to control CAM. These data suggest that angiogenic switch in MM may involve loss of an endogenous angiogenesis inhibitor, such as endostatin. [source] Increased serum levels of endostatin in patients with idiopathic pulmonary fibrosisJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 4 2005Masaaki Sumi Abstract Endostatin is an angiogenesis inhibitor that is an endogenously produced proteolytic fragment of type XVIII collagen. Serum levels of endostatin have been studied extensively in patients with malignant diseases. Recently, elevated serum endostatin levels were observed in patients with systemic sclerosis accompanying pulmonary fibrosis. To determine whether elevated serum endostatin can be observed in patients with idiopathic pulmonary fibrosis (IPF), we measured serum levels of endostatin in 69 patients with benign respiratory disease using an ELISA kit. The median of the serum endostatin levels in these patients was 50.8 pg/mL. Seven of 11 patients (63.6%) with collagen disease-associated pulmonary fibrosis (CDPF), and 19 of 24 patients (79.2%) with IPF had higher serum endostatin levels than the median level of the 69 patients. There was no statistical difference in serum endostatin levels between the patients with IPF and those with CDPF (P=0.7898). Serum endostatin levels in 24 patients with IPF were significantly higher than those in 34 patients with respiratory diseases other than IPF and CDPF (P=0.0001). Elevated serum levels of endostatin were observed in patients with IPF. Although the mechanisms are unclear, elevated serum levels of endostatin may be related to the fibrosing process in the lung. J. Clin. Lab. Anal. 19:146,149, 2005. © 2005 Wiley-Liss, Inc. [source] Decreased expressions of thrombospondin 2 in cyclosporin A-induced gingival overgrowthJOURNAL OF PERIODONTAL RESEARCH, Issue 2 2004Jeong Tae Koh Objectives:, Cyclosporin A (CsA) is known to elicit fibrous gingival overgrowth with changes of blood vessel profiles. In this study, we examined the expression of several angiogenic and angiostatic genes during the development of CsA-induced gingival overgrowth. Methods:, For the development of gingival overgrowth, Sprague-Dawley rats received subcutaneous injections of CsA in daily doses of 5, 10, 15 mg/kg body weight for 6 weeks, and another group received 10 mg/kg of CsA for 3, 6, and 12 weeks. Human gingival tissues were obtained from three CsA-treated patients following the gingivectomy procedure and from three healthy patients following the crown-lengthening procedure as a control. Gingival fibroblasts were isolated from the healthy gingival tissues of the rat or the human, and cultured with 250,1000 ng/ml of CsA. Results:, Reverse transcription,polymerase chain reaction (RT,PCR) analyses showed that expressions of some angiogenic genes such as angiopoietin 1, basic fibroblast growth factor, and vascular endothelial growth factor, and angiostatic genes such as angiopoietin 2, brain-specific angiogenesis inhibitor 1 and 2, and thrombospondin 1 were not changed significantly in both gingival tissues and cultured fibroblast cells under the CsA treatments. However, expression of thrombospondin 2 (TSP2) decreased dose- and time-dependently in rat and human gingival tissues. Western blot analyses showed that the expression of TSP2 protein was dose-dependently reduced by the CsA treatments in human cultured gingival fibroblasts. Conclusions:, These results indicate that the decrease in angiostatic TSP2 expression may be attributed to the CsA-induced gingival vascularization rather than to the increased expression of angiogenic genes. It suggests that TSP2 is involved in the development of CsA-induced gingival overgrowth with the gingival vascularization. [source] Thrombin induces neoangiogenesis in the chick chorioallantoic membraneJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003M. Caunt Summary., Most tumors have constitutively active tissue factor on their surface, capable of generating thrombin in the surrounding environment, and thrombosis is associated with cancer. Thrombin is known to induce a malignant phenotype by enhancing tissue adhesion and cell growth in vitro and in vivo in mice. Because tumors require angiogenesis for growth, we examined whether thrombin induces neoangiogenesis in a physiologically intact in vivo model. Thrombin (0.1 U mL,1) induced neoangiogenesis in the chick chorioallantoic membrane over a 24,72-h period by approximately 2,3-fold. This was inhibited by the potent thrombin inhibitor, hirudin and shown to have its mode of action by ligation of the thrombin protease-activated receptor, PAR-1. The thrombin receptor activation peptide, SFLLRNPNDKYEPF (200 µm) also enhanced neoangiogenesis c. 2,3-fold. Thrombin-induced neoangiogenesis was accompanied by the induction of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) mRNA at 24,48 h (approximately 2-fold) as determined by semi-quantitative reverse transcriptase-polymerase chain reaction. Thrombin-induced neoangiogenesis was inhibited to baseline level by the specific angiogenesis receptor inhibitors KDR-Fc (vs. VEGF) and Tie-2-Fc (vs. Ang-1 and Ang-2), as well as the non-specific angiogenesis inhibitor thrombospondin-1. Thrombin-induced neoangiogenesis was also inhibited to baseline level by agents known to inhibit thrombin receptor signaling in other cells: G-coupled protein receptor inhibitor, pertussis toxin (40 pg per egg), protein kinase C inhibitor, bisindolylmaleimide (1 µm per egg), MAP kinase inhibitor, PD980598 (10 µm per egg) and PI3 kinase inhibitor, LY294002 (0.25 µm per egg). Thus angiogenesis is stimulated by thrombosis, which could help explain the enhancement of experimental tumorigenesis by thrombin. [source] Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cellsCANCER SCIENCE, Issue 10 2009Noritaka Ohga The polyphenol epigallocatechin-3 gallate (EGCG) in green tea suppresses tumor growth by direct action on tumor cells and by inhibition of angiogenesis, but it is not known whether it specifically inhibits tumor angiogenesis. We examined the anti-angiogenic effect of EGCG on tumor-associated endothelial cells (TEC), endothelial progenitor cells (EPC), and normal endothelial cells (NEC). EGCG suppressed the migration of TEC and EPC but not NEC. EGCG also inhibited the phosphorylation of Akt in TEC but not in NEC. Furthermore, vascular endothelial growth factor-induced mobilization of EPC into circulation was inhibited by EGCG. MMP-9 in the bone marrow plasma plays key roles in EPC mobilization into circulation. We observed that expression of MMP-9 mRNA was downregulated by EGCG in mouse bone marrow stromal cells. In an in vivo model, EGCG suppressed growth of melanoma and reduced microvessel density. Our study showed that EGCG has selective anti-angiogenic effects on TEC and EPC. It is suggested that EGCG could be a promising angiogenesis inhibitor for cancer therapy. (Cancer Sci 2009; 100: 1963,1970) [source] NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeuticsCANCER SCIENCE, Issue 4 2003Kunio Matsumoto Invasion and subsequent establishment of metastasis are devastating events for patients with cancer, but past therapeutic approaches have paid relatively little attention to these important issues. Hepatocyte growth factor (HGF) and its receptor, the c-Met tyrosine kinase, play roles in cancer invasion and metastasis in a wide variety of tumor cells. Activation of the c-Met receptor integrates multiple signal transduction pathways involved in cell-cell and cell-matrix interactions, cellular migration, and breakdown of the extracellular scaffold. Paracrine activation of the c-Met receptor by stromal-derived HGF mediates tumor-stromal interactions that facilitate invasion and metastasis. Likewise, aberrant expression of the c-Met receptor and autocrine or mutational activation of c-Met receptor tyrosine kinase are closely associated with the progression of malignant tumors. Based on this background, NK4, a competitive antagonist of HGF-c-Met association was prepared so as to block cancer invasion and metastasis. NK4, an internal fragment of HGF, binds to but does not activate the c-Met receptor, thereby competitively antagonizing the biological activities of HGF. Unexpectedly, NK4 was subsequently shown to be an angiogenesis inhibitor as well, and this angioinhibitory activity is independent of its action as an HGF-antagonist. Importantly, NK4 protein or NK4 gene therapy have been shown to inhibit tumor invasion, metastasis and angiogenesis, effectively converting malignant tumors into benign tumors. Targeting tumor invasion-metastasis and angiogenesis with NK4 seems to have considerable therapeutic potential for cancer patients. (Cancer Sci 2003; 94: 321,327) [source] Challenges of antiangiogenic cancer therapy: trials and errors, and renewed hopeJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2007Miguel Ángel Medina ,,Introduction ,,What can we learn from the previous failures? ,,Signs of hope ,,Another turn of the screw: a surrogate marker, at last ,,Future avenues for the vascular therapy of cancer Abstract Angiogenesis inhibition has been proposed as a general strategy to fight cancer. However, in spite of the promising preclinical results, a first generation of antiangiogenic compounds yielded poor results in clinical trials. Conceptual errors and mistakes in the design of trials and in the definition of clinical end-points could account for these negative results. In this context of discouraging results, a second generation of antiangiogenic therapies is showing positive results in phases II and III trials at the beginning of the twenty-first century. In fact, several combined treatments with conventional chemotherapy and antiangiogenic compounds have been recently approved. The discovery and pharmacological development of future generations of angiogenesis inhibitors will benefit from further advances in the understanding of the mechanisms involved in human angiogenesis. New styles of trials are necessary, to avoid missing potential therapeutic effects. Different clinical end-points, new surrogate biomarkers and methods of imaging will be helpful in this process. Real efficacy in clinical trials may come with the combined use of antiangiogenic agents with conventional chemotherapy or radiotherapy, and combinations of several antiangiogenic compounds with different mechanisms of action. Finally, the existing antiangiogenic strategies should include other approaches such as vascular targeting or angioprevention. [source] Decrease in Tumor Apparent Permeability-Surface Area Product to a MRI Macromolecular Contrast Medium Following Angiogenesis Inhibition with Correlations to Cytotoxic Drug AccumulationMICROCIRCULATION, Issue 5 2004HEIKE E. DALDRUP-LINK ABSTRACT Background: New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (KPS) in tumors to a macromolecular contrast medium (MMCM), to follow changes in KPS induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin. Methods: Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)30) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate KPS. These estimates of KPS were correlated with cytotoxic drug accumulations in the tumors. Results: Anti-VEGF treatment reduced KPS to MMCM in tumor tissue from 0.013 mL h,1 cm,3 (n = 9) at baseline to 0.003 mL h,1 cm,3 (n = 9) 24 h later (p < .05). The KPS values correlated significantly (r2 = .78; p < .0001) with the tumor cisplatin accumulation. No correlation (r2 = .001; p = .89) was found between KPS and tumor accumulation of the substantially smaller 5-FU molecule. Conclusions: MMCM-enhanced MRI can be used to detect and estimate changes in KPS to this contrast agent following a single dose of anti-VEGF antibody. The decline in KPS induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration. [source] Hemostatic complications of angiogenesis inhibitors in cancer patients,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2008Francesca Elice Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] Gallic acid is partially responsible for the antiangiogenic activities of Rubus leaf extractPHYTOTHERAPY RESEARCH, Issue 9 2006Zhijun Liu Abstract An aqueous extract of leaves from Rubus suavissimus S. Lee (Rosaceae) or sweet leaf tea was tested for antiangiogenic activity in a human tissue-based ,brin,thrombin clot angiogenesis assay. Further fractionation of this crude extract was performed and the antiangiogenic effect of individual fractions was assessed. The extract was also tested for its oral bioavailability by using the serum of normal rats gavaged with the extract in the assay. At a 0.1% w/v concentration, the extract inhibited initiation of the angiogenic response and subsequent neovessel growth from samples that had already initiated an angiogenic response. Two subfractions of the extract showed signi,cant inhibition of angiogenesis at 0.1% w/w. Gallic acid was elucidated as one of the active angiogenesis inhibitors in one fraction. A 1 mm concentration of gallic acid totally inhibited angiogenesis. In the form of leaf extract, a one-tenth concentration produced the same total inhibition as pure gallic acid. The 10-fold difference in potency suggests the presence of other active compounds contributing to the overall antiangiogenic effect of the extract. The oral absorption of this extract was tested by using serum from rats given the extract orally (gavage) in the angiogenesis assay system. The serum of rats orally administered the sweet leaf tea extract at doses of 0.1% w/w and 0.3% w/w did not signi,cantly inhibit angiogenesis. However, the serum of rats injected intraperitoneally at a dose of 0.1% w/w caused a 41% inhibition of angiogenesis compared with saline injected controls. These preliminary results warrant further bioassay directed identi,cation of other responsible compounds. Copyright © 2006 John Wiley & Sons, Ltd. [source] Gastrointestinal oncological surgery in patients with metastatic cancer treated with angiogenesis inhibitors: safe or not?ANZ JOURNAL OF SURGERY, Issue 10 2009Terence C. Chua BScMed (Hons) No abstract is available for this article. [source] Dermatological aspects of angiogenesisBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2002P. Velasco Summary Neovascularization is vital for the growth of tumours, providing a lifeline for sustenance and waste disposal. Tumour vessels can grow by sprouting, intussusception or by incorporating bone marrow-derived endothelial precursor cells into growing vessels. Recent advances in vascular biology have identified some key factors that control vascular growth, and have led to the hypothesis that in normal tissues vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. In contrast, increased secretion of angiogenic factors and the down-regulation of endogenous angiogenesis inhibitors induce tumour angiogenesis. Vascular quiescence in the skin seems to be primarily maintained by a balance between the endogenous angiogenesis inhibitors thrombospondin 1 and thrombospondin 2 and the potent proangiogenic factor vascular endothelial growth factor A. Inhibiting tumour growth by controlling angiogenesis is an intriguing approach with great potential for the treatment of vascular tumours such as haemangioma, Kaposi's sarcoma and solid cutaneous tumours such as squamous cell carcinoma, melanoma and basal cell carcinoma. In this review, the role of angiogenesis and more recent topics such as lymphangiogenesis in cutaneous tumour growth, invasion and metastasis will be discussed. [source] Role of hematopoietic lineage cells as accessory components in blood vessel formationCANCER SCIENCE, Issue 7 2006Nobuyuki Takakura In adults, the vasculature is normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. However, blood vessels in adults retain the capacity for brisk initiation of angiogenesis, the growth of new vessels from pre-existing vessels, during tissue repair and in numerous diseases, including inflammation and cancer. Because of the role of angiogenesis in tumor growth, many new cancer therapies are being conducted against tumor angiogenesis. It is thought that these anti-angiogenic therapies destroy the tumor vessels, thereby depriving the tumor of oxygen and nutrients. Therefore, a better understanding of the molecular mechanisms in the process of sprouting angiogenesis may lead to more effective therapies not only for cancer but also for diseases involving abnormal vasculature. It is widely believed that after birth, endothelial cells (EC) in new blood vessels are derived from resident EC of pre-existing vessels. However, evidence is now emerging that cells derived from the bone marrow may also contribute to postnatal angiogenesis. Most studies have focused initially on the contribution of endothelial progenitor cells in this process. However, we have proposed a concept in which cells of the hematopoietic lineage are mobilized and then entrapped in peripheral tissues, where they function as accessory cells that promote the sprouting of resident EC by releasing angiogenic signals. Most recently we found that hematopoietic cells play major roles in tumor angiogenesis by initiating sprouting angiogenesis and also in maturation of blood vessels in the fibrous cap of tumors. Therefore, manipulating these entrapment signals may offer therapeutic opportunities to stimulate or inhibit angiogenesis. (Cancer Sci 2006; 97: 568,574) [source] | ||||||||||