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PubMed2000

2.5 kDa and 5.0 kDa heparin fragments specifically inhibit microvessel sprouting and network formation in VEGF165-mediated mammalian angiogenesis.

Tumour growth is angiogenesis dependent. Thrombosis and thromboembolism are very common in cancer patients. These patients are often treated with heparin as an anti-coagulant. Many tumour angiogens, including VEGF165, and endogenous anti-angiogenesis factors bind heparin tightly. Using the non-surgical mesenteric-window angiogenesis assay, we studied in detail the systemic effect of heparin fractions with a mean MW of 2.5, 5.0 and 16.4 kDa on the microvessel sprouting and network formation in angiogenesis mediated by VEGF165 in rats. The microvessel network was assessed objectively in terms of the number and lengths of segments (the distance between two successive branching points), the number of branching points, the degree of tortuosity, the index of interconnecting loop formation, the index of intersection, as well as the number and lengths of sprouts. Compared with the saline control, the 2.5 kDa fraction significantly shortened the microvessel sprouts and the microvessel segments but increased the microvessel tortuosity in statistical terms; the 5.0 kDa fraction statistically significantly shortened the sprouts, decreased the number of segments and the number of microvessel branching points; whereas the 16.4 kDa fraction statistically significantly elongated the longest segments. Moreover, statistically significant differences were found between the three heparin fractions in terms of microvessel tortuosity (2.5 vs. 16.4 kDa), index of loop formation (5.0 vs. 2.5 + 16.4 kDa) and index of intersection (5.0 vs. 16.4 kDa). These findings demonstrate that heparin fragments size-specifically inhibit microvessel sprouting and network formation in VEGF165-mediated angiogenesis. As VEGF165 is a potent angiogen in human tumours, we suggest that heparin enriched in 2.5 kDa species and 5.0 kDa species especially should be exploited as a combined anti-coagulant and specific adjuvant anti-angiogenic agent in cancer patients who require anti-coagulant therapy.

Angiogenesis Inhibitors↗
PubMed2000

A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma.

Angiogenesis is the formation of new blood vessels and occurs physiologically during embryonal growth, wound healing and during the menstrual cycle. It is essential for the proliferation and metastases of most malignant neoplasms. Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value in the disease. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are expressed by myeloma cells and appear to play a role in the increased angiogenesis seen in myeloma. In addition, VEGF may serve as a paracrine growth factor for myeloma cells. Based on the increased angiogenesis observed in myeloma, thalidomide has been studied as antiangiogenic therapy. Although its mechanism of action in myeloma is still unclear, thalidomide appears to be active in 25-30% of patients with refractory myeloma. Major toxicities include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine its role as initial treatment for myeloma. This paper reviews the available data on angiogenesis in myeloma, and summarizes the role of thalidomide therapy in this disease. The pharmacology and toxicity of thalidomide are also discussed.

Angiogenesis Inhibitors↗
PubMed2005

Targeting vascular endothelial growth factor and angiogenesis for the treatment of colorectal cancer.

Angiogenesis, the development and proliferation of new blood vessels, is critical for the growth of tumors. The process of new blood vessel formation is under complex control from a variety of pro- and anti-angiogenesis factors. By identifying and understanding these factors, new therapies have been developed to inhibit tumor growth and survival by blocking tumor-related angiogenesis. Recent success with the monoclonal antibody against vascular endothelial growth factor (VEGF; bevacizumab) in a large, randomized, phase III study has provided a critical proof of principle for this therapeutic area. This review will outline the biology of angiogenesis in colorectal cancer and discuss the current status of angiogenesis inhibition in its treatment.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Clinical perspectives of tumor angiogenesis in pediatric oncology.

Angiogenesis, the formation of new capillaries from existing blood vessels, is necessary for embryonic growth and development. It is also seen later during the female cycle and wound healing, but is virtually absent otherwise in the healthy adult organism. Angiogenesis is again observed under pathological conditions, like for example in solid pediatric malignancies. Once grown to a diameter of several millimeters, the latter depend on angiogenesis in order to further grow and to metastasize. Recent experimental and clinical evidence suggests 1) that the extent of tumor angiogenesis could serve to predict clinical outcome and 2) that the inhibition of angiogenesis could be a means to improve the conventional therapy of solid pediatric malignancies.

Adult↗
PubMed2002

A fragment of human TrpRS as a potent antagonist of ocular angiogenesis.

Pathological angiogenesis contributes directly to profound loss of vision associated with many diseases of the eye. Recent work suggests that human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) link protein synthesis to signal transduction pathways including angiogenesis. In this study, we show that a recombinant form of a COOH-terminal fragment of TrpRS is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in a mouse model and of naturally occurring retinal angiogenesis in the neonatal mouse. The angiostatic activity is dose-dependent in both systems. The recombinant fragment is similar in size to one generated naturally by alternative splicing and can be produced by proteolysis of the full-length protein. In contrast, the full-length protein is inactive as an antagonist of angiogenesis. These results suggest that fragments of TrpRS, as naturally occurring and potentially nonimmunogenic anti-angiogenics, can be used for the treatment of neovascular eye diseases.

Alternative Splicing↗
PubMed2005

Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay.

Anti-angiogenic strategies are emerging as an important tool for the treatment of cancer and inflammatory diseases. In the present investigation we isolated several isoflavones from a tempeh (fermented soyabean) extract. The isolated isoflavones were identified as 5,7,4'-trihydroxyisoflavone (genistein), 7,4'-dihydroxyisoflavone (daidzein), 6,7,4'-trihydroxyisoflavone (factor 2), 7,8,4'-trihydroxyisoflavone (7,8,4'-TriOH) and 5,7,3',4'-tetrahydroxyisoflavone (orobol). The effects on angiogenesis of these isoflavones were evaluated in the chicken chorioallantoic membrane assay; their capacity to inhibit vascular endothelial growth factor-induced endothelial cell proliferation and expression of the Ets 1 transcription factor, known to be implicated in the regulation of new blood vessel formation, were also investigated. We found that all isoflavones inhibited angiogenesis, albeit with different potencies. Compared with negative controls, which slightly inhibited in vivo angiogenesis by 6.30 %, genistein reduced angiogenesis by 75.09 %, followed by orobol (67.96 %), factor 2 (56.77 %), daidzein (48.98 %) and 7,8,4'-TriOH (24.42 %). These compounds also inhibited endothelial cell proliferation, with orobol causing the greatest inhibition at lower concentrations. The isoflavones also inhibited Ets 1 expression, providing some insight into the molecular mechanisms of their action. Furthermore, the chemical structure of the different isoflavones suggests a structure-activity relationship. Our present findings suggest that the new isoflavones might be added to the list of low molecular mass therapeutic agents for the inhibition of angiogenesis.

Angiogenesis Inhibitors↗
PubMed2006

On metronomic chemotherapy: modulation of angiogenesis mediated by VEGE-A.

Tumors are angiogenesis dependent. Preclinical studies have shown that well-tolerated continuous low dose, i.e. metronomic, chemotherapy can exert significant antiangiogenic effects per se and thereby a greater antitumor influence than conventional chemotherapy with high, spaced-out bolus doses. There are however, no means of quantitatively assessing the antiangiogenic effect of chemotherapy in tumors. We therefore used a surrogate tumor-free, non-surgical rat mesentery model and quantitatively studied the dose effect of metronomic treatment with cisplatin, cyclophosphamide, doxorubicin, fluorouracil and paclitaxel on VEGF-A-mediated angiogenesis, a characteristic of tumors. Cyclophosphamide and paclitaxel treatment exerted significant dose-dependent antiangiogenic effects, whereas doxorubicin treatment produced insignificant effects. By contrast, metronomic cisplatin and fluorouracil treatment occasionally significantly stimulated angiogenesis in a dose-dependent, non-linear manner. To our knowledge, this is the first report of metronomic chemotherapy stimulating angiogenesis in vivo. The data suggest that the angiogenic response to cisplatin, cyclophosphamide, fluorouracil and paclitaxel was significantly influenced by the presence of antioxidants in the vehicles or when co-treated with N-acetylcystein, a widely used free-radical scavenger. The data relating to the metronomic scheduling were compared with bolus treatment data for the identical agent formulations in the same experimental model. Cisplatin, cyclophosphamide and paclitaxel caused approximately the same overall, agent-specific angiogenesis-modulating effects following metronomic and bolus treatments. Moreover, apparently secondary delayed effects of chemotherapy affected capillary sprouting.

Acetylcysteine↗
PubMed2001

Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2.

Cyclosporin A (CsA) is an immunosuppressive drug that inhibits the activity of transcription factors of the nuclear factor of activated T cells (NFAT) family, interfering with the induction of cytokines and other inducible genes required for the immune response. Here we show that CsA inhibits migration of primary endothelial cells and angiogenesis induced by vascular endothelial growth factor (VEGF); this effect appears to be mediated through the inhibition of cyclooxygenase (Cox)-2, the transcription of which is activated by VEGF in primary endothelial cells. Consistent with this, we show that the induction of Cox-2 gene expression by VEGF requires NFAT activation. Most important, the CsA-mediated inhibition of angiogenesis both in vitro and in vivo was comparable to the Cox-2 inhibitor NS-398, and reversed by prostaglandin E(2). Furthermore, the in vivo corneal angiogenesis induced by VEGF, but not by basic fibroblast growth factor, was selectively inhibited in mice treated with CsA systemically. These findings involve NFAT in the regulation of Cox-2 in endothelial cells, point to a role for this transcription factor in angiogenesis, and may provide a novel mechanism underlying the beneficial effects of CsA in angiogenesis-related diseases such as rheumatoid arthritis and psoriasis.

Angiogenesis Inhibitors↗
PubMed2003

Hemostatic regulators of tumor angiogenesis: a source of antiangiogenic agents for cancer treatment?

The maintenance of vascular integrity and control of blood loss are regulated by a sophisticated system of circulating and cell-associated hemostatic factors. These factors control local platelet aggregation, the conversion of soluble fibrinogen to an insoluble fibrin polymer, and the dissolution of fibrin. However, hemostatic factors are also involved in a number of physiologic processes, including development, tissue remodeling, wound repair, reproduction, inflammation, and angiogenesis. In this review, we outline ways in which angiogenesis is coordinated with and regulated by hemostasis. We focus on inhibitors of angiogenesis contained within platelets or harbored as cryptic fragments of hemostatic proteins and assess the experimental and preclinical evidence for their ability to inhibit tumor angiogenesis and, thus, their potential to be anticancer agents. Finally, we review the results of recent clinical trials involving angiogenesis inhibitors and the evidence that antiangiogenic therapy may be associated with hemostatic complications.

Angiogenesis Inhibitors↗
PubMed2004

XR5967, a novel modulator of plasminogen activator inhibitor-1 activity, suppresses tumor cell invasion and angiogenesis in vitro.

Recent reports suggest that elevated levels of plasminogen activator inhibitor (PAI)-1 may contribute to tumor progression. We have recently shown that antibodies to PAI-1 block the invasive and migratory potential of human fibrosarcoma cells and suppress angiogenesis in vitro. Here we report the in vitro evaluation of a low-molecular-weight modulator of PAI-1, XR5967, on invasion, migration and angiogenesis. XR5967, a diketopiperazine, dose-dependently inhibited the activity of human and murine PAI-1, towards urokinase plasminogen activator (uPA), with IC50 values of 800 nM and 8.3 microM, respectively. This was confirmed by SDS-PAGE, revealing that XR5967 inhibited complex formation between PAI-1 and uPA. This suppression may be caused by XR5967 promoting insertion of the reactive center loop within PAI-1. XR5967 dose-dependently inhibited the invasion of human HT1080 fibrosarcoma cells through Matrigel. Their invasion was reduced by 57% (p<0.001) at 5 microM. HT1080 cell migration was inhibited in a similar manner, indicating that PAI-1 may play an additional role in invasion, which is distinct to its role in the regulation of proteolysis. The potential of XR5967 to inhibit the invasion/migration of human endothelial cells was investigated in an in vitro model of angiogenesis. In this model XR5967 reduced tubule formation by 77% at 5 microM (p<0.001), highlighting a crucial role for PAI-1 in angiogenesis. These data stress the importance of a balanced proteolysis in the processes of invasion, migration and angiogenesis. Our results support the clinical findings and indicate that modulation of PAI-1 activity, with low-molecular-weight inhibitor of PAI-1 activity, may be of therapeutic benefit for the treatment of cancer.

Angiogenesis Inhibitors↗
PubMed2006

The future of therapeutic myocardial angiogenesis.

Despite improvements in its medical and surgical management, ischemic coronary disease remains responsible for significant morbidity, mortality, and economic burden in developed nations. Therapeutic myocardial angiogenesis is an attractive treatment option for patients with end-stage coronary disease who have failed percutaneous and surgical methods of revascularization. Over the past decade, our understanding of the biology of new blood vessel formation has improved significantly, and consequently, the use of growth factors to induce myocardial angiogenesis has been attempted in preclinical and clinical trials. Although growth factor therapy had demonstrated tremendous success in animal models, clinical trials have shown limited benefit in patients with coronary disease. Vascular endothelial growth factors and fibroblast growth factors are perhaps the most potent inducers of angiogenesis that have been used in animal models, and the only ones that have been used in clinical trials. This review outlines the biology of new vessel formation and the effects of these growth factors in the context of myocardial angiogenesis with an emphasis on the effects on the endothelium. It also provides a brief overview of delivery strategies and summarizes the preclinical and clinical evidence relating to exogenous growth factor delivery for myocardial angiogenesis. Lastly, we discuss the limitations and future challenges of angiogenic therapy.

Angiogenesis Inducing Agents↗
PubMed2003

Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules.

Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non-sprouting (the enlargement, splitting, and fusion of pre-existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non-small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti-tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti-tumor potential in preclinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials.

Angiogenesis Inhibitors↗
PubMed2004

Mast cell contribution to angiogenesis related to tumour progression.

The current wisdom is that tumours are endowed with an angiogenic capability and that their growth, invasion and metastasis are angiogenesis dependent. It is now well documented that neoplastic cells are influenced by their microenvironment and vice versa. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion and survival. Tumour cells are surrounded by an infiltrate of inflammatory cells, namely lymphocytes, neutrophils, macrophages and mast cells (MCs), which communicate via a complex network of intercellular signalling pathways, mediated by surface adhesion molecules, cytokines and their receptors. This review article summarizes: (i) the MC mediators involved in angiogenesis; (ii) the experimental evidence concerning the role played by MCs in angiogenesis; (iii) the list of solid and haematological tumours in which a close relationship between angiogenesis, tumour progression and MCs has been demonstrated; (iv) the circumstances in which MCs are a critical source of angiogenic factors in vivo, and in such cases, the signals that regulate their production and secretion that need to be determined as a prelude to the elaboration of new therapeutic strategies associated with MC presence and activation.

Angiogenesis Inducing Agents↗
PubMed2004

TNP-470, an angiogenesis inhibitor, suppresses the progression of peritoneal fibrosis in mouse experimental model.

BACKGROUND: In patients on long-term peritoneal dialysis (PD), angiogenesis and vasculopathy are observed in the peritoneum, and the degree of vascularization correlates with the area of fibrotic tissue, suggesting the involvement of angiogenesis in the progression of peritoneal fibrosis. The aim of the present study was to evaluate the effect of TNP-470, an anti-angiogenic compound, on the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG). METHODS: Peritoneal fibrosis was induced by injection of CG into peritoneal cavity of Institute for Cancer Research (ICR) mice. TNP-470 was injected subcutaneously with CG. Mice were sacrificed, and peritoneal tissues were dissected out at days eight and 16 after CG and TNP-470 injection. The expression patterns of CD31 (as a marker of endothelial cells), vascular endothelial cell growth factor (VEGF), alpha-smooth muscle actin (as a marker of myofibroblasts), heat shock protein 47 (HSP47), type III collagen, F4/80 (as a marker of mice macrophages), proliferating cell nuclear antigen (PCNA), and cyclin-dependent kinase 2 (Cdk2) were examined by immunohistochemistry. RESULTS: CG-injected mice showed thickening of the submesothelial zone and increased number of vessels, myofibroblasts, and infiltrating macrophages. The expression levels of VEGF, type III collagen, and HSP47 were increased, and a large number of PCNA-positive cells and Cdk2-expressing cells were observed in the thickened submesothelial area. Treatment with TNP-470 suppressed the submesothelial zone thickening and reduced collagen III expression as well as angiogenesis. TNP-470 also decreased the number of VEGF-expressing cells, myofibroblasts, macrophages, PCNA-positive cells, and Cdk2-expressing cells. CONCLUSION: Our results indicate the involvement of angiogenesis in the progression of peritoneal fibrosis, and suggest that TNP-470 may be potentially useful for the prevention of peritoneal fibrosis through inhibition of angiogenesis and suppression of myofibroblast proliferation.

Actins↗
PubMedDate not supplied

Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases.

Angiogenesis, the formation of new vessels, is important in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. Chemotactic cytokines termed chemokines mediate the ingress of leukocytes, including neutrophils and monocytes into the inflamed synovium. In this review, authors discuss the role of the most important angiogenic factors and angiogenesis inhibitors, as well as relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. RA was chosen as a prototype to discuss these issues, as the majority of studies on the role of angiogenesis and chemokines in inflammatory diseases were carried out in arthritis. However, other systemic inflammatory (autoimmune) diseases including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM) and systemic vasculites are also discussed in this context. As a number of chemokines may also play a role in neovascularization, this issue is also described here. Apart from discussing the pathogenic role of angiogenesis and chemokines, authors also review the regulation of angiogenesis and chemokine production by other inflammatory mediators, as well as the important relevance of neovascularization and chemokines for antirheumatic intervention.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Angiogenesis inhibitors found within the haemostasis pathway.

Angiogenesis, the development of new blood vessels from the existing vasculature, and haemostasis, the coagulation cascade leading to formation of a clot, are among the most consistent host responses associated with cancer. Importantly, these two pathways interrelate, with blood coagulation and fibrinolysis influencing tumor angiogenesis directly, thereby contributing to tumor growth. Moreover, many endogenous inhibitors of angiogenesis are found within platelets or harboured as cryptic fragments of haemostatic proteins. In this review we outline ways in which angiogenesis is coordinated and regulated by haemostasis in human cancer. Then we detail the experimental and pre-clinical evidence for the ability of many of these endogenous proteins to inhibit tumor angiogenesis and thus their potential to be anti-cancer agents, with particular reference to any clinical trials.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Endogenous angiogenesis inhibitors.

When the FDA commissioner announced in February 2004 the approval of Avastin for the treatment of patients with colon cancer, he called angiogenesis inhibitors a fourth modality of anti-cancer therapy. Because angiogenesis inhibitors are relatively less toxic than conventional chemotherapy and have a lower risk of drug resistance, they may also represent a new class of anti-cancer agents, some of which have sufficiently reduced toxicity that they may be safely used long term. These include immunotherapy, vaccines, telomerase inhibitors, apoptosis inducers, low dose metronomic chemotherapy, novel hormonal therapies, gene therapy and others. However, at least 16 endogenous angiogenesis inhibitors have been discovered in the circulation, and/or in the extracellular matrix. These may become the safest and least toxic of anti-cancer therapies. Four are already being administered by injection in clinical trials for cancer. Recently, it has been reported that at least two endogenous angiogenesis inhibitors can be significantly increased in humans (endostatin), and in mice (thrombospondin), by oral administration of small molecules which themselves are already FDA approved for other uses. This finding suggests several new clinical applications for the future, including the possibility of guiding the use of angiogenesis inhibitors by blood or urinary biomarkers, currently being developed, that may detect the presence of cancer before it is symptomatic, or before it can be located by conventional methods.

Angiogenesis Inhibitors↗
PubMed2006

Angiogenesis blockade as a new therapeutic approach to experimental colitis.

BACKGROUND: Neoangiogenesis is a critical component of chronic inflammatory disorders. Inhibition of angiogenesis is an effective treatment in animal models of inflammation, but has not been tested in experimental colitis. AIM: To investigate the effect of ATN-161, an anti-angiogenic compound, on the course of experimental murine colitis. METHOD: Interleukin 10-deficient (IL10(-/-)) mice and wild-type mice were kept in ultra-barrier facilities (UBF) or conventional housing, and used for experimental conditions. Dextran sodium sulphate (DSS)-treated mice were used as a model of acute colitis. Mice were treated with ATN-161 or its scrambled peptide ATN-163. Mucosal neoangiogenesis and mean vascular density (MVD) were assessed by CD31 staining. A Disease Activity Index (DAI) was determined, and the severity of colitis was determined by a histological score. Colonic cytokine production was measured by ELISA, and lamina propria mononuclear cell proliferation by thymidine incorporation. RESULT: MVD increased in parallel with disease progression in IL10(-/-) mice kept in conventional housing, but not in IL10(-/-) mice kept in UBF. Angiogenesis also occurred in DSS-treated animals. IL10(-/-) mice with established disease treated with ATN-161, but not with ATN-163, showed a significant and progressive decrease in DAI. The histological colitis score was significantly lower in ATN-161-treated mice than in scrambled peptide-treated mice. Inhibition of angiogenesis was confirmed by a significant decrease of MVD in ATN-161-treated mice than in ATN-163-treated mice. No therapeutic effects were observed in the DSS model of colitis. ATN-161 showed no direct immunomodulatory activity in vitro. CONCLUSION: Active angiogenesis occurs in the gut of IL10(-/-) and DSS-treated colitic mice and parallels disease progression. ATN-161 effectively decreases angiogenesis as well as clinical severity and histological inflammation in IL10(-/-) mice but not in the DDS model of inflammatory bowel disease (IBD). The results provide the rational basis for considering anti-angiogenic strategies in the treatment of IBD in humans.

Acute Disease↗