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At least 397 records · Page 22Linked to original sources
PubMed2004

Angiogenesis of gastrointestinal tumours and their metastases--a target for intervention?

Angiogenesis is an obligatory event for the growth of tumours beyond 2 mm in diameter, above which simple oxygen diffusion can no longer support the rapid proliferation of malignant cells. Angiogenesis is a fine balance between inhibitory and stimulatory factors, the knowledge of which offers novel targets for the treatment of gastrointestinal neoplasia. A literature search of Pubmed and Medline databases was undertaken, using the keywords colorectal cancer, pancreatic cancer, gastrointestinal cancer, angiogenesis and anti-angiogenesis therapy. It was found that angiogenesis in primary tumours is a sequential and highly complex cascade of molecular events resulting in the rapid exponential growth of the tumour. Hepatic metastases of primary tumours may be less reliant on traditional angiogenic pathways, by co-opting pre-existing hepatic vasculature. Research into angiogenesis has revealed many different sites that can be targeted by agents such as tyrosine kinase inhibitors. Many anti-angiogenic agents are undergoing preclinical evaluation, with only a few entering phase I and phase III clinical trials. However, early results suggest that anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia.

Angiogenesis Inhibitors↗
PubMed2006

Cancer CXC chemokine networks and tumour angiogenesis.

Chemokines have pleiotropic effects in regulating immunity, angiogenesis, stem cell trafficking, and mediating organ-specific metastases of cancer. In the context of angiogenesis, the CXC chemokine family is a unique group of cytokines known for their ability to behave in a disparate manner in the regulation of angiogenesis. The glutamic acid-leucine-arginine (ELR+) CXC chemokines are potent promoters of angiogenesis, and mediate their angiogenic activity via signal-coupling of CXCR2 on endothelium. By contrast, members of the CXC chemokine family, such as platelet factor-4 (PF4; CXCL4) and interferon-inducible CXC chemokines are potent inhibitors of angiogenesis, and use CXCR3 on endothelium to mediate their angiostatic activity. This review will discuss the biology of CXC chemokines in the context of angiogenesis related to cancer.

Angiogenesis Inhibitors↗
PubMed2006

Inhibition of in vivo angiogenesis by N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine.

N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD), an antibacterial substance isolated from the flesh fly, inhibits human tumor growth in the nude mice model; however, the mechanism of its action is unclear. The in vivo antitumor effect includes the inhibition of tumor cell proliferation and suppression of angiogenesis. Angiogenesis is essential for tumor growth in vivo. In this study, we examined whether 5-S-GAD inhibits tumor cell-induced angiogenesis by performing the mouse dorsal air sac assay. We found that intraperitoneal administration of 5-S-GAD inhibited the angiogenesis induced by S180 mouse sarcoma cells. Furthermore, 5-S-GAD also inhibited vascular endothelial growth factor-induced angiogenesis in the Matrigel plug assay and embryonic angiogenesis in the chick embryo chorioallantoic membrane assay. However, 5-S-GAD did not show any effect on the proliferation, migration, and tube formation of vascular endothelial cells. These results provide the first evidence that a bioactive substance derived from the flesh fly has antiangiogenic activity in vivo, although the mechanisms involved could not be explained.

Angiogenesis Inhibitors↗
PubMed2005

Inhibition of tumor angiogenesis by a natural fragment of a tRNA synthetase.

Human tyrosyl- and tryptophanyl-tRNA synthetases (TyrRS and TrpRS, respectively) link protein synthesis to signal-transduction pathways, including angiogenesis. Fragments of TyrRS stimulate angiogenesis, whereas those of TrpRS (T2-TrpRS) inhibit angiogenesis. Thus, these two synthetases acquired opposing activities during evolution, possibly as a coordinated mechanism for regulating angiogenesis. The recent identification of the cellular target of T2-TrpRS sheds light into the mechanism of angiogenesis inhibition. This mechanism provides a molecular basis for the lack of effect of T2-TrpRS on the normal vasculature. With these features, we suggest that this fragment of a tRNA synthetase might safely be used to arrest neovascularization of tumors. In particular, an anti-angiogenesis agent that stops the growth of tumor vessels without affecting normal vessels might serve as an adjunct to cytotoxic therapy.

Angiogenesis Inhibitors↗
PubMed2006

Therapeutic angiogenesis: translating experimental concepts to medically relevant goals.

Angiogenesis is central to many physiological and pathological phenomena. In physiological angiogenesis, new vessels are well shaped and their growth is finely tuned to match the metabolic needs of tributary tissues. Accordingly, neovascularization is activated by physical exercise and destabilized by non-use. In contrast, pathological blood vessels that are observed in retinal neovascularization, cancer or in ischemic tissues are leaky, irregularly shaped, and tend to form arterial-venous fistulae. A great deal of attention is focused on new approaches for medical manipulation of vascular growth. These methods are aimed at facilitating the reperfusion of ischemic tissues or eradicating pathological vasculature. In this position paper, we challenge the rationale of therapeutic angiogenesis for the cure of myocardial and peripheral ischemia. Therapeutic angiogenesis aims at combating the insufficiency of, or insensitivity to angiogenic factors in the setting of atherosclerotic-induced arterial occlusion. However, clinical evidence indicates that such a defect is not common among patients with ischemic disease, as a whole. Genetic and environmental factors could account for the great heterogeneity in the expression of the master angiogenic factors. Future improvements in the strategy would require the introduction of in vitro assays and in vivo imaging systems for assessing human angiogenesis. Finally, the promise is to find individualized angiogenesis-based therapies for a genuine cure of ischemia and prevention of organ failure.

Angiogenesis Inducing Agents↗
PubMed2003

Infectious angiogenesis: Bartonella bacilliformis infection results in endothelial production of angiopoetin-2 and epidermal production of vascular endothelial growth factor.

Pathological angiogenesis, the development of a microvasculature by neoplastic processes, is a critical component of the development of tumors. The role of oncogenes in the induction of angiogenesis has been extensively studied in benign and malignant tumors. However, the role of infection in inducing angiogenesis is not well understood. Verruga peruana is a clinical syndrome caused by the bacterium Bartonella bacilliformis, and is characterized by the development of hemangioma-like lesions, in which bacteria colonize endothelial cells. To gain insight into how this bacteria induces angiogenesis in vivo, we performed in situ hybridization of clinical specimens of verruga peruana for the angiogenesis factors vascular endothelial growth factor (VEGF), its receptors VEGFR1 and VEGFR2, and angiopoietin-2. High-level expression of angiopoietin-2 and VEGF receptors was observed in the endothelium of verruga peruana. Surprisingly, the major source of VEGF production in verruga peruana is the overlying epidermis. Infection of cultured endothelium with B. bacilliformis also resulted in induction of angiopoetin-2 in vitro. These findings imply a collaboration between infected endothelium and overlying epidermis to induce angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2001

Angiogenesis-dependent diseases.

There is accumulating evidence that leukemias and other hematologic diseases are angiogenesis-dependent. Therefore, angiogenesis inhibitors may be useful adjuncts to conventional therapies in the treatment of these diseases. When all conventional therapy has failed, an angiogenesis inhibitor may be successfully used alone, as has been demonstrated in the treatment of multiple myeloma by thalidomide. The experimental and clinical evidence that the efficacy of thalidomide against multiple myeloma is mediated in part by its antiangiogenic activity is presented here. In current clinical trials throughout the United States, angiogenesis inhibitors are being used against cancer in combination with conventional chemotherapy or radiotherapy. Angiogenesis inhibitors are also being used in combination with each other. This practice may increase as different angiogenesis inhibitors become more widely available.

Angiogenesis Inhibitors↗
PubMed2002

Tea catechins inhibit angiogenesis in vitro, measured by human endothelial cell growth, migration and tube formation, through inhibition of VEGF receptor binding.

We have investigated whether tea catechins (EC, ECg, EGC, EGCg) have any inhibitory effects on angiogenesis and which step they affect during the process. The effects of catechins were tested on in vitro models of angiogenesis, namely, growth, migration and tube formation of human umbilical vein endothelial cells. All four catechins inhibited angiogenesis in vitro in the three different bioassays with concentrations ranging from 1.56 to 100 microM. Among the four catechins tested, epigallocatechin gallate (EGCg) was the most effective in inhibiting angiogenesis in all three assays. When these four catechins were tested on VEGF binding assay, only EGCg inhibited the binding of VEGF, a major angiogenesis inducing factor, to endothelial cells in a concentration dependent manner. These results indicate that while all four tea catechins inhibit the process of angiogenesis, EGCg alone can reduce the binding of VEGF to its receptors and thus affects the downstream signaling.

Angiogenesis Inhibitors↗
PubMed2003

NO and angiogenesis.

Angiogenesis requires the elaboration of endothelium-derived nitric oxide (NO). Angiogenic factors induce the release of NO from endothelial cells, which mediates a multiplicity of processes involved in angiogenesis. These NO-modulated processes include endothelial cell survival, proliferation, migration, and interaction with the extracellular matrix. Derangements of the NO synthase pathway impair angiogenesis. Accordingly, the competitive inhibitor of the NOS pathway asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of angiogenesis. By contrast, agents which increase NO synthesis, such as low dose statins, enhance angiogenesis. Modulation of the NO synthase pathway could become a new therapeutic avenue for angiogenesis-related disorders.

Angiogenesis Inhibitors↗
PubMed2001

Prevention of fracture healing in rats by an inhibitor of angiogenesis.

Angiogenesis is considered essential to fracture healing, but its role in the healing process remains poorly understood. Angiogenesis inhibitors, which block new blood vessel formation by specifically targeting vascular cells, are currently under development for use in cancer chemotherapy, and are potentially powerful tools for defining the consequences of angiogenic impairment on fracture healing. In this study, we directly tested the effects of the angiogenesis inhibitor TNP-470 on the healing of closed femoral fractures in an established rat model system. Beginning 1 day after fracture, animals received either angiogenesis inhibitor at a therapeutically effective antitumor dose, or a weight-adjusted amount of carrier vehicle. The progress of fracture healing was assessed at weekly intervals for 21 days by radiography and histology; functional assessment was carried out at day 24 by biomechanical testing. By all three criteria, treatment with the angiogenesis inhibitor completely prevented fracture healing. Formation of both callus and periosteal woven bone were suppressed, indicating that both the intramembranous and endochondral pathways of osteogenesis were affected. The resulting tissue resembled "atrophic nonunions" often seen clinically in cases of failed fracture healing, but rarely achieved in animal models. These results show that angiogenesis is essential to very early stages of fracture healing, and suggest this model system may be useful for understanding the mechanisms underlying fracture nonunions due to vascular impairment. Finally, the data raise the possibility that impairment of fracture healing may be an adverse effect of clinical treatments with antiangiogenic drugs.

Angiogenesis Inhibitors↗
PubMed2002

Evidence for the causal role of endogenous interferon-alpha/beta in the regulation of angiogenesis, tumorigenicity, and metastasis of cutaneous neoplasms.

Primary tumor growth and metastasis depend on angiogenesis, which is determined by the balance between proangiogenic and antiangiogenic molecules. Interferon (IFN)-alpha and -beta inhibit angiogenesis through downregulation of interleukin-8, matrix metalloproteinase-9, and basic fibroblast growth factor. To provide evidence for the causal role of IFN-alpha/beta in the induction of neoplasms, their angiogenesis, and hence, progressive growth, we carried out experiments using 129S6 IFN-alpha/beta receptor -/- mice back-crossed to BALB/c nude mice. Subcutaneous angiogenesis was determined following implantation of gelfoam sponges containing 0.4% agarose and several proangiogenic molecules. Tumorigenicity and production of lung metastasis were determined subsequent to subcutaneous and intravenous injections, respectively, of highly metastatic A375SM human melanoma cells. Carcinogenesis was induced by chronic exposure of mice to UVB radiation (5 kJ/m2, 3 times/week). Angiogenesis, tumorigenicity, and production of metastasis, as well as development of autochthonous skin tumors, were all accelerated in IFN-alpha/beta receptor -/- mice as compared to control mice. Collectively, the data show that inability to respond to endogenous IFN-alpha/beta (through a mutation in the IFN-alpha/beta receptor) leads to increased susceptibility to carcinogenesis, enhanced angiogenesis, tumorigenicity, and metastasis.

Angiogenesis Inhibitors↗
PubMed2004

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.

Angiogenesis Inhibitors↗
PubMed2002

A tricistronic retroviral vector expressing natural antiangiogenic factors inhibits angiogenesis in vitro, but is not able to block tumor progression in vivo.

Angiogenesis, the formation of new blood vessels out of pre-existing capillaries, is essential for tumor progression. Many factors have been identified that are able to inhibit angiogenesis. Here, we report the construction of a tricistronic retroviral vector encoding two inhibitors of angiogenesis expressed in mammals: the N-terminal fragment of rat prolactin (16KrPRL) and a secreted form of human platelet factor 4 (sPF4). When transduced by this retroviral vector, a rat glioblastoma cell line loses its ability of promoting endothelial cell locomotion, the initial step of angiogenesis, and the formation of an endothelial cell tube network. In spite of this encouraging in vitro result, however, the anti-angiogenic vector cannot block glioblastoma progression in animal models. These results suggest that therapeutic strategies aiming to block tumor progression through the inhibition of tumor-associated angiogenesis, should not only provide large numbers of angiogenesis inhibitors, but also target the angiogenic factors produced by tumor cells. Moreover, the data described herein may confirm recent findings from other groups which indicate that in order to successfully counteract tumor progression, drugs inhibiting new blood vessel formation should be employed in combination with traditional anti-tumor strategies, such as chemotherapy or radiotherapy.

Angiogenesis Inhibitors↗
PubMed2002

Dermatological aspects of angiogenesis.

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.

Angiogenesis Inhibitors↗
PubMed2002

Effect of venous ulcer exudates on angiogenesis in vitro.

BACKGROUND: Angiogenesis, the formation of new from existing capillaries, is an important mechanism in venous ulcer healing. The aim of this study was to determine whether venous leg ulcer wound exudates stimulate or inhibit angiogenesis. METHODS: Fluid exudate was obtained from 16 venous ulcers over a 4-h interval. Five of the ulcers had not healed after more than 1 year of compression bandaging, and five were rapidly healing ulcers. As a control, acute wound fluids were collected from subcutaneous drains in seven patients. Vascular endothelial growth factor (VEGF) at 2 ng/ml acted as a positive control. Tubules stained with an antiendothelial antibody were quantified using an image analysis system. The extent of angiogenesis was expressed as the ratio of the mean tubule length in the test wells over that in blank control wells. RESULTS: Venous ulcer exudates significantly inhibited angiogenesis (mean (95 per cent confidence interval) 0.72 (0.48 to 0.96)) compared with acute wound fluids (2.48 (0.86 to 4.10)) (P < 0.002) and VEGF (1.47 (1.32 to 1.61)) (P = 0.01). Exudates from the five non-healing venous ulcers inhibited angiogenesis (0.31 (0.15 to 0.46)) significantly more than exudates from the five rapidly healing venous ulcers (0.93 (0.21 to 1.65)) (P = 0.03). CONCLUSION: Fluid exudate from venous ulcers, in particular those that healed slowly, inhibited experimental angiogenesis in this study.

Adult↗
PubMed2002

Angiogenesis inhibitors in clinical development for lung cancer.

The use of tumor angiogenesis as a therapeutic target is based on extensive literature showing the dependence of tumors on the process of angiogenesis for growth, invasion, and metastasis. Seminal work performed by Folkman three decades ago determined that tumors beyond the size of approximately 2 mm require angiogenesis for subsequent growth and development. This basic hypothesis stimulated research in the field of angiogenesis and has resulted in the identification of factors that both enhance and inhibit this "angiogenic switch." The intent of this article is to present data on several angiogenesis inhibitors that are currently undergoing clinical evaluation in cancer patients. These agents may be particularly useful in the treatment of lung cancer, both as adjunctive therapy in early-stage or locally advanced disease, as well as in combination strategies with platinum-based therapy in metastatic disease. Although angiogenesis inhibitors have been in clinical trials for the past decade, there has been a shift in recent years towards the development of more mechanism-based and receptor-targeted agents. Interestingly, no antiangiogenic agent has been approved as such for use in cancer, perhaps because of the challenges involved in the clinical development of these novel agents. These include the potential requirement for long-term administration, difficulties in deriving biologically efficacious doses in early clinical trials, and the inability to use tumor regression as a primary endpoint in phase II trials.

Angiogenesis Inhibitors↗
PubMed2002

Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications.

Angiogenesis, or formation of new blood vessels from pre-existing ones, is essential for normal development and wound healing/reproductive functions in adults. Abnormal regulation of angiogenesis has been implicated in the pathogenesis of several disorders, including cancer. Vascular endothelial growth factor (VEGF)-A is a pivotal stimulator of angiogenesis because its binding to VEGF receptors has been shown to promote endothelial cell migration and proliferation, two key features required for the development of new blood vessels. In addition, VEGF-A increases vascular permeability, which may also contribute to angiogenesis and tumor growth. Recognition of the central role of VEGF-A in angiogenesis has led to the hypothesis that its inhibition may represent a novel and effective approach to the treatment of cancer and other conditions characterized by pathologic angiogenesis. Several lines of evidence support this idea, and early clinical experience with the humanized anti-VEGF-A monoclonal antibody bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA) has been encouraging. Clinical efficacy of antiangiogenic therapy with bevacizumab is being evaluated in several phase 3 trials in various types of cancer, as well as in patients with age-related macular degeneration.

Angiogenesis Inhibitors↗
PubMed2003

Angiogenesis in Waldenstrom's macroglobulinemia.

Angiogenesis has been associated with disease progression and poor prognosis in several hematologic malignancies including multiple myeloma. In this article, we summarize the rationale for studying angiogenesis in plasma cell disorders including Waldenstrom's macroglobulinemia (WM). We also discuss the results of a study of angiogenesis in WM conducted at the Mayo Clinic. Our study shows that only 30% of patients with WM had increased (intermediate- or high-grade) angiogenesis. A weak correlation was found between mean microvessel density (MVD) and marrow infiltration. Unlike multiple myeloma, MVD and angiogenesis grade were not predictive factors for survival. Although these findings suggest that angiogenesis may not be a major factor in WM, it does not exclude a paracrine role for angiogenic cytokines or the study of antiangiogenic agents in this disease.

Angiogenesis Inhibitors↗