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At least 865 records · Page 48Linked to original sources
PubMed1997

An overview of clinical trials involving inhibitors of angiogenesis and their mechanism of action.

Angiogenesis is a biologic process whereby endothelial cells divide and migrate to form new blood vessels. This process is required in physiological conditions, but is also a necessary requirement for solid tumors to grow and metastasize. Over the last several years, the growth factors that have both a positive and negative influence on tumor angiogenesis have been delineated. Interfering with tumor angiogenesis was considered a potential therapeutic strategy 25 years ago, but only recently have compounds with an ability to interfere with angiogenesis entered clinical trials. This review will discuss the first generation of angiogenesis inhibitors, their mechanism of action and data from clinical trials.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs.

It has become well accepted that solid tumors must create a vascular system for nutrient delivery and waste removal in order to grow appreciably. This process, angiogenesis, is critical to the progression of gliomas, with vascular changes accompanying the advancement of these tumors. The cascade of events in this process of blood vessel formation involves a complex interplay between tumor cells, endothelial cells, and their surrounding basement membranes in which enzymatic degradation of surrounding ground substance and subsequent endothelial cell migration, proliferation, and tube formation occurs. It is likely that a host of growth factors is responsible for mediating these key events. To date, a role for Vascular Endothelial Growth Factor (VEGF) in glioma angiogenesis has been convincingly demonstrated. This review explores the contribution of other growth factors--Fibroblast Growth Factors (FGFs), Platelet-Derived Growth Factor (PDGF), Epidermal Growth Factor (EGF), and Transforming Growth Factors (TGFs)--to glioma angiogenesis. These growth factors may influence glioma angiogenesis by directly stimulating endothelial cell proliferation, by mediating the expression of key proteases on endothelial cells necessary for angiogenesis, or by regulating the expression of VEGF and of each other.

Animals↗
PubMedDate not supplied

Physiology of angiogenesis.

Angiogenesis is a key prerequisite for growth in all vertebrate embryos and in many tumors. Rapid growth requires efficient transport of oxygen and metabolites. Hence, for a better understanding of tissue growth, biophysical properties of vascular systems, in addition to their molecular mechanisms, need to be investigated. The purpose of this article is twofold: (1) to discuss the biophysics of growing and perfused vascular systems in general, emphasizing non-sprouting angiogenesis and remodeling of vascular plexuses; and (2) to report on cellular details of sprouting angiogenesis in the initially non-perfused embryonic brain and spinal cord. It is concluded that (1) evolutionary optimization of the circulatory system corresponds to highly conserved vascular patterns and angiogenetic mechanisms; (2) deterministic and random processes contribute to both extraembryonic and central nervous system vascularization; (3) endothelial cells interact with a variety of periendothelial cells during angiogenesis and remodeling; and that (4) mathematical models integrating molecular, morphological and biophysical expertise improve our understanding of normal and pathological angiogenesis and account for allometric relations.

Allantois↗
PubMedDate not supplied

Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling.

Two distinct mechanisms, vasculogenesis and angiogenesis implement the formation of the vascular network in the embryo. Vasculogenesis gives rise to the heart and the first primitive vascular plexus inside the embryo and in its surrounding membranes, as the yolk sac circulation. Angiogenesis is responsible for the remodeling and expansion of this network. While vasculogenesis refers to in situ differentiation and growth of blood vessels from mesodermal derived hemangioblasts, angiogenesis comprises two different mechanisms: endothelial sprouting and intussusceptive microvascular growth (IMG). The sprouting process is based on endothelial cell migration, proliferation and tube formation. IMG divides existing vessel lumens by formation and insertion of tissue folds and columns of interstitial tissue into the vessel lumen. The latter are termed interstitial or inter-vascular tissue structures (ITSs) and tissue pillars or posts. Intussusception also includes the establishment of new vessels by in situ loop formation in the wall of large veins. The molecular regulation of these distinct mechanisms is discussed in respect to the most important positive regulators, vascular endothelial growth factor (VEGF) and its receptors flk-1 (KDR) and flt-1, the Angiopoietin/tie system and the ephrin-B/EpH-B system. The cellular mechanisms and the molecular regulation of angiogenesis in the pathological state are summarized and the differences of physiological and pathological angiogenesis elaborated.

Angiopoietin-1↗
PubMed1999

A novel approach for studying angiogenesis: a human skin equivalent with a capillary-like network.

Angiogenesis results from an ordered set of events that can be modulated in vivo by a variety of angiogenesis-enhancing or inhibiting agents. We review in vitro angiogenesis models and the agents that enhance or inhibit angiogenesis. We also discuss a new in vitro angiogenesis model created within a skin equivalent. Briefly, endothelial cells were combined with the cutaneous cells of a standard skin equivalent and cultured in a chitosan cross-linked collagen-glycosaminoglycan scaffold of this endothelialized skin. This model enables the formation of capillary-like structures in a coculture environment containing newly synthesized extracellular matrix by fibroblasts and keratinocytes. Several morphological characteristics associated with the microvasculature in vivo were observed in the endothelialized skin equivalent such as histotypic organization of tubular structures, basement membrane deposition, and intercellular junction formation.

Animals↗
PubMed1999

Regulation of angiogenesis and endothelial cell motility by matrix-bound fibroblasts.

This study sought to examine the effect of matrix-bound fibroblasts on angiogenesis and endothelial cell motility. Promotion of angiogenesis by matrix-bound fibroblasts was assessed using rat aortic ring and endothelial tube formation assays. Enhancement of human endothelial cell motility by matrix-bound fibroblasts was assessed using cytodex-2 bead and colloidal gold phagokinetic motility assays. Antibody to hepatocyte growth factor/scatter factor (HGF/SF) but not vascular endothelial growth factor (VEGf) decreased fibroblast-enhanced motility of endothelial cells. The promotion of tube formation by matrix-bound fibroblasts was neutralised with antibodies to HGF/SF and VEGf, both known promoters of angiogenesis. HGF/SF presence was detected by ELISA; whilst the presence of VEGf was detected by Western blotting. These data show that matrix-embedded fibroblasts regulate the motility of vascular endothelial cells and enhance angiogenesis, an effect partly attributed to production of angiogenesis-promoting cytokines HGF/SF and/or VEGf.

Journal Article↗
PubMed1999

Inhibition of angiogenesis and tumor growth by murine 7E3, the parent antibody of c7E3 Fab (abciximab; ReoPro).

Angiogenesis plays an essential role in the growth and dissemination of solid tumor cancers. The expression of endothelial cell integrin alpha(v)beta3 has been shown to increase during vascular proliferation associated with human tumors. Selective antagonists of alpha(v)beta3 can block angiogenesis and tumor growth by inducing programmed cell death in proliferating endothelial cells. Monoclonal antibody 7E3, an antagonist of the human, but not murine, integrins alpha(v)beta3 and alphaIIbbeta3 (GPIIb/IIIa), inhibits platelet aggregation. It is the parent antibody of a mouse/human chimeric antibody fragment approved for adjunctive therapy of patients undergoing percutaneous coronary interventions to prevent ischemic complications (c7E3Fab; abciximab; ReoPro). To evaluate the potential of 7E3 to inhibit human angiogenesis and tumor growth independent of its antiplatelet effects, we established integrin alpha(v)beta3-negative human melanoma tumors in full-thickness human skin grafted onto SCID mice. The resulting tumors induce a human angiogenic response as assessed by the immunoreactivity of vascular cells with monoclonal antibodies specific for human CD31. Administration of 7E3 prevented or significantly inhibited the growth of tumors, and this effect correlated with a significant reduction in the number of blood vessels supplying the tumors. These results support the previous findings that blockade of integrin alpha(v)beta3 inhibits angiogenesis and tumor growth and indicates that dual inhibitors of alpha(v)beta3 and alphaIIbbeta3 are effective in blocking tumor growth and angiogenesis.

Journal Article↗
PubMed1999

Antibody against murine PECAM-1 inhibits tumor angiogenesis in mice.

Platelet endothelial cell adhesion molecule (PECAM-1/CD31), a member of the immunoglobulin superfamily expressed at high levels on endothelial cells, has been recently implicated in angiogenesis. Although antagonism of PECAM-1 inhibited neovascularization in two different animal models of growth factor/chemokine-induced angiogenesis, its participation in tumor angiogenesis has not been established. We therefore investigated its involvement in models of tumor angiogenesis in mice. An antibody against murine PECAM-1 that was shown to block in vitro murine endothelial tube formation inhibited the subcutaneous growth and tumor vascularity of three tumors in mice: A549 human non-small cell lung cancer in SCID mice, B16 murine melanoma in C57BL/6 mice and AB12 murine mesothelioma in Balb/c mice. These studies suggest a possible role for PECAM-1 in the complex process of tumor angiogenesis and provide additional evidence of the importance of endothelial cell adhesion molecules to the formation of new vessels.

Journal Article↗
PubMed2001

Angiogenesis as a predictor of long-term survival for 377 Japanese patients with breast cancer.

Angiogenesis. as assessed by microvessels, has been a common prognostic indicator for breast cancer in the last decade. However, the significance of angiogenesis remains controversial. This is a retrospective study of 377 Japanese patients selected from 663 breast cancer patients operated on between 1971 and 1987. To evaluate an objective method to quantify microvessel density in angiogenesis, we employed average microvessel count (AMC) per square millimeter. We investigated five factors: angiogenesis, lymph-node status (n), clinical tumor size (T), histological grade (HG). and tumor necrosis (TN), followed for a median of 10 years. Sixty-seven patients (17.8%) had recurrence and 54 patients (14.3%) died of breast cancer. Univariate analysis showed that n, T, HG. and AMC (P = 0.0020) were significantly predictive of 20-year relapse-free survival (RFS). n, T, and HG were significantly associated with 20-year overall survival (OS) but AMC was borderline significant (P = 0.0630). Multivariate analysis for RFS and OS showed that n. T. HG, and AMC (P < 0.0001, P = 0.0033, respectively) were all significant and independent prognostic factors. When stratified by T or n, a significant impact of AMC on RFS or OS was seen both in patients with T2 and T3 carcinomas or in node-negative patients, but not in T1 or node-positive patients. Thus, we can confirm angiogenesis as a significant independent prognostic factor associated with longterm survival in Japanese breast cancer patients, especially in node-negative patients and in patients with T2 and T3 carcinomas.

Adolescent↗
PubMed2001

An ex vivo angiogenesis assay utilizing commercial porcine carotid artery: modification of the rat aortic ring assay.

The study of angiogenesis as a therapeutic target requires a reliable, physiologically relevant, and technically straightforward assay. An ex vivo assay bridges the gap between cell-based assays, which may not realistically represent the complex process of vessel sprouting, and in vivo assays, which are time consuming and expensive. Porcine carotid arteries provide an ideal tissue source for angiogenesis inhibitor screens due to their availability, physiological relevance and large size. 1.5 mm2 fragments of porcine carotid arteries were incubated in 48-well culture plates and sandwiched between two 100 microliters layers of Matrigel. Sprouting was observed from the explants and quantitated, using a digital imaging system, after two weeks of incubation. Histological analysis using Factor VIII-related antigen (von Willebrand Factor) as an endothelial cell-specific marker identified these sprouts, which were consistent with endothelial cell morphology, supporting the system as a model of angiogenesis. Accordingly, the angiogenesis inhibitors suramin, 2-methoxyestradiol, and the matrix metalloprotease inhibitor Batimastat were shown to completely inhibit sprouting at 50, 0.5, and 5.0 micrograms/ml, respectively and to have ED50 values of 23, 0.15, and 0.14 microgram/ml. This assay shows good reproducibility and eliminates animal to animal variation. The system should prove adaptable to other forms of angiogenic stimulation, ultimately making a variety of assays for angiogenesis available to laboratories of limited resources.

2-Methoxyestradiol↗
PubMed2001

Feto-maternal interface of human placenta inhibits angiogenesis in the chick chorioallantoic membrane (CAM) assay.

The rapidly growing chorionic villi of the human placenta characteristically show constant blood vessel growth and differentiation. In contrast, the underlying decidua reveals tissue remodeling without apparent angiogenesis. Using the chick chorioallantoic membrane (CAM) assay, we found marked inhibition of angiogenesis by the feto-maternal interface tissue derived from nine human placentas obtained minutes after delivery. Inhibition was prevented by the addition of monensin, which blocks the release of synthesized cell products, and was markedly reduced by drying or freezing the tissue before the assay. Histology, combined with statistical analysis of the constituent cell types, correlated inhibition of angiogenesis with the number of fetally-derived extravillous trophoblasts in the feto-maternal interface tissue. Electron microscopy revealed endothelial cell damage in preexisting small (but not large) CAM vessels. We conclude that decidual tissue inhibited angiogenesis by releasing a water soluble factor which was under apparent constant production by vaible trophoblast on the CAM. The extravillous trophoblast population resembles tumor cells in its migratory and invasive properties but, in contrast to tumor induced angiogenesis, it is angiostatic, perhaps to counteract angiogenic proteins leaking from the intervillous space which could be detrimental to the maternal organism if active.

Allantois↗
PubMed2000

Role of incipient angiogenesis in cancer metastasis.

Metastasis is the primary cause of mortality in cancer patients. Angiogenesis is intimately involved in metastasis at the site of entry of tumor cells into the vasculature and at the site of eventual metastasis growth. In this commentary, we review current paradigms regarding angiogenesis in metastatic sites. Recent discoveries challenge some of the existing paradigms. Significant prior data suggest that successful formation of metastases requires: 1) angiogenesis in the primary tumor site; 2) downregulation of cohesive molecules and tumor cell increased motility, resulting in invasion into neovessels; 3) tumor cell embolism; 4) arrest and attachment in capillary beds of distant organs; 5) extravasation and proliferation in the organ parenchyma; and 6) re-establishment of angiogenesis when the tumor reaches > 1-2 mm in size [1]. While most recent data largely confirm the aforementioned sequence of events, a few reports have revealed new knowledge about the earliest phases of angiogenesis of metastases. Of particular importance has been the ability to create tumor cell lines that are stably transfected with reporter genes, such as green fluorescence protein. With these tools it is now literally possible to monitor tumor formation from a single cell [2-7].

Animals↗
PubMed1999

Zebrafish angiogenesis: a new model for drug screening.

Angiogenesis is necessary for tumor growth, making inhibition of vessel formation an excellent target for cancer therapy. Current assays for angiogenesis, however, are too complex to be practical for drug screening. Here, we demonstrate that the zebrafish is a viable whole animal model for screening small molecules that affect blood vessel formation. Blood vessel patterning is highly characteristic in the developing zebrafish embryo and the subintestinal vessels (SIVs) can be stained and visualized microscopically as a primary screen for compounds that affect angiogenesis. Small molecules added directly to the fish culture media diffuse into the embryo and induce observable, dose-dependent effects. To evaluate the zebrafish as a model, we used two angiogenesis inhibitors, SU5416 and TNP470, both of which have been tested in mammalian systems. Both compounds caused a reduction in vessel formation when introduced to zebrafish embryos prior to the onset of angiogenesis. Short duration (1 h) exposure of SU5416 was sufficient to block new angiogenic and vasculogenic vessel formation. In contrast, TNP470 required continuous exposure to block SIV formation and had no apparent effect on vasculogenic vessel formation. To ascertain whether blood vessels in the zebrafish embryo respond to angiogenic compounds, we introduced human VEGF into embryos. Injection of VEGF caused an observable increase in SIV formation.

Journal Article↗
PubMed2003

The role of the fibrinolytic system in corneal angiogenesis.

The plasminogen activation system has been implicated in angiogenesis and angiogenesis-dependent diseases such as cancer, atherosclerosis and ocular diseases. The identification and development of inhibitors of angiogenesis offer new possibilities for the treatment of these diseases. To clarify the role of proteins involved in the regulation of fibrinolysis during corneal angiogenesis, we have studied corneal vessel formation in mice deficient for urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). Our results corroborate earlier findings that angiogenesis in the mouse cornea is dependent on PAI-1 and plasminogen. The absence of tPA, uPA or TAFI did not affect the formation of new vessels in the cornea.

Animals↗
PubMedDate not supplied

Oral administration of a nitric oxide synthase inhibitor enhances de novo mammalian angiogenesis mediated by TNF-alpha, saline and mast-cell secretion.

In healthy adult rats, the test tissue that is used in the mesenteric-window angiogenesis assay is natively vascularized, lacks physiological angiogenesis, and is unperturbed by surgical intervention. Using the rat MWAA oral treatment with the nitric oxide (NO) synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) enhanced the angiogenic response (compared with controls receiving the inactive enantiomer D-NAME) following i.p. injections of (i) TNF-alpha at an approximate physiological dose, (ii) Compound 48/80, which is a highly selective secretagogue causing mast-cell secretion in situ and a very strong angiogenic response, and (iii) saline of a grade not made for infusion, causing a weak angiogenic response. Angiogenesis was assessed quantitatively using microscopic morphometry and image analysis in terms of objective variables recording the microvascular spatial extension, microvascular density, number and length of microvessel segments (extending between two successive branching points) and the degree of microvessel tortuosity. The data strongly suggest that endogenous NO inhibits all three mammalian angiogenesis reactions, although to a markedly different extent. Notably, the present data are virtually the opposite of those that have been reported from other mammalian angiogenesis models, the test tissues of which display deranged homeostasis, such as surgical intervention and/or ischemia.

Administration, Oral↗
PubMed1999

Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.

Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.

Angiostatins↗
PubMed1993

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.

The development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation. Blood vessel neoformation is also important in the pathogenesis of many disorders, particularly rapid growth and metastasis of solid tumours. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-alpha and transforming factors-alpha and -beta. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosarcoma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells in vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

Animals↗
PubMed2001

The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor.

Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.

Animals↗