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At least 721 records · Page 40Linked to original sources
PubMed2004

Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor.

A small synthetic library of cyclohexapeptidomimetic calixarenes was prepared to identify disrupters of vascular endothelial growth factor (VEGF) binding to its receptor that inhibits angiogenesis. From this library, we discovered GFA-116, which potently inhibits (125)I-VEGF binding to Flk-1 in Flk-1-overexpressing NIH 3T3 cells and human prostate tumor cells with an IC(50) of 750 nM. This inhibition is highly selective for VEGF in that (125)I- platelet-derived growth factor binding to its receptor is not affected. GFA-116 inhibits VEGF-stimulated Flk-1 tyrosine phosphorylation and subsequent activation of Erk1/2 mitogen-activated protein kinases. Furthermore, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor-dependent stimulation of Erk1/2 phosphorylation are not affected at concentrations as high as 10 microM. In vitro, GFA-116 inhibits angiogenesis as measured by inhibition of migration and formation of capillary-like structures by human endothelial cells as well as suppression of microvessel outgrowth in rat aortic rings and rat cornea angiogenesis. In vivo, GFA-116 (50 mpk/day) inhibits tumor growth and angiogenesis as measured by CD31 staining of A-549 human lung tumors in nude mice. Furthermore, GFA-116 is also effective at inhibiting tumor growth and metastasis to the lung of B16-F10 melanoma cells injected into immunocompetent mice. Taken together, these results demonstrate that a synthetic molecule capable of disrupting the binding of VEGF to its receptor selectively inhibits VEGF-dependent signaling and suppresses angiogenesis and tumorigenesis.

Angiogenesis Inhibitors↗
PubMed2004

The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584.

Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. Vascular endothelial growth factor (VEGF) and VEGF receptors represent critical molecular targets for antiangiogenesis therapy. In this study, we investigated the biological effect of the histone deacetylase inhibitor NVP-LAQ824 in combination with the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on tumor growth and angiogenesis. We report that treatment with NVP-LAQ824 affected tumor and endothelial cells and was associated with increased histone acetylation, p21 up-regulation, and growth inhibition. In addition, NVP-LAQ824 treatment inhibited the expression of angiogenesis-related genes such as angiopoietin-2, Tie-2, and survivin in endothelial cells and down-regulated hypoxia-inducible factor 1-alpha and VEGF expression in tumor cells. Combination treatment with NVP-LAQ824 and PTK787/ZK222584 was more effective than single agents in inhibiting in vitro and in vivo VEGF-induced angiogenesis. Endothelial cell proliferation, tube formation, and invasion into the Matrigel plugs were reduced. In mouse models with established subcutaneous prostate (PC3) and orthotopic breast tumors (MDA-MB321), this combination treatment induced 80 to 85% inhibition of tumor growth without overt toxicity. These results suggest that the combination of histone deacetylase inhibitors and VEGF receptor inhibitors may target multiple pathways in tumor progression and angiogenesis and represents a novel therapeutic approach in cancer treatment.

Angiogenesis Inhibitors↗
PubMed2004

Angiogenesis and tumor proliferation/metastasis of human colorectal cancer cell line SW620 transfected with endocrine glands-derived-vascular endothelial growth factor, as a new angiogenic factor.

Endocrine glands-derived-vascular endothelial growth factor (EG-VEGF) was recently cloned as a new angiogenic factor that selectively acts on the endothelium of endocrine gland cells. We evaluated the involvement of EG-VEGF in colorectal cancer. The expression of EG-VEGF was confirmed in all of the colorectal cancer cell lines. (On the other hand, the expression of EG-VEGF mRNA was not detected in colorectal normal mucosae.) Stable EG-VEGF infectors of colorectal cancer cell line SW620 were produced, EG-VEGF transfectants were implanted into cecum and s.c., and cell proliferation was evaluated. Angiogenesis was evaluated by dorsal air sac method. Liver metastasis was evaluated after the implantation of EG-VEGF transfectants into the mouse spleen. Tumor proliferation (cecum, s.c.) was significantly higher in the EG-VEGF transfectants than in the control cells. The small vessels were significantly increased in EG-VEGF transfectants as compared with those in control cells. Also, liver metastatic ratio was higher in the EG-VEGF transfectants than in the control cells. In this study, EG-VEGF, a new angiogenic factor, may lead to angiogenesis, promoting cell proliferation and liver metastasis in colorectal cancers. When the EG-VEGF gene-overexpressing colorectal cancer cell line that had been treated with phosphorothioate antisense EG-VEGF oligonucleotides was injected s.c. into mice, angiogenesis and tumor growth were inhibited. Although the novel angiogenesis factor EG-VEGF was not expressed in the normal colorectal mucosa, it was expressed in colorectal cancer cells, which indicates that it is a cancer-specific and possibly tissue-specific angiogenesis factor in the large intestine, and which suggests that it can be targeted by a novel antiangiogenesis therapy.

Angiogenesis Inducing Agents↗
PubMed2006

Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589.

PURPOSE: Angiogenesis is required for tumor progression and represents a rational target for therapeutic intervention. Histone deacetylase (HDAC) inhibitors have been shown to have activity against various tumor cell types by inhibiting proliferation and inducing apoptosis both in vitro and in vivo. HDAC inhibitors have also been reported to inhibit angiogenesis. The goal of this study was to characterize the antiangiogenic and antitumor activity of a recently developed HDAC inhibitor, the hydroxamic derivative LBH589. MATERIALS AND METHODS: To evaluate the antiangiogenesis activity of LBH589, we did cell cycle analysis, cell proliferation, tube formation, invasion assays in vitro, and Matrigel plug assay in vivo. To determine the antitumor activity of LBH589, we established human prostate carcinoma cell PC-3 xenografts in vivo. To evaluate the effect of LBH589 on endothelial signaling pathways, gene expression, and protein acetylation, we did Western blots and reverse transcription-PCR in human umbilical vein endothelial cells (HUVEC). Immunohistochemical analysis was done to evaluate new blood vessel formation in vivo. RESULTS: LBH589 induced acetylation of histone H3 and alpha-tubulin protein in HUVECs. Histone and nonhistone protein acetylation correlated with induction of G(2)-M cell cycle arrest, inhibition of HUVEC proliferation, and viability. Noncytotoxic concentrations of LBH589 inhibited endothelial tube formation, Matrigel invasion, AKT, extracellular signal-regulated kinase 1/2 phosphorylation, and chemokine receptor CXCR4 expression. In vivo dosing of mice with LBH589 (10 mg/kg/d) reduced angiogenesis and PC-3 tumor growth. CONCLUSION: This study provides evidence that LBH589 induces a wide range of effects on endothelial cells that lead to inhibition of tumor angiogenesis. These results support the role of HDAC inhibitors as a therapeutic strategy to target both the tumor and endothelial compartment and warrant the clinical development of these agents in combination with angiogenesis inhibitors.

Acetylation↗
PubMed2004

Angiogenesis-dependent and independent phases of intimal hyperplasia.

BACKGROUND: Neointimal vascular smooth muscle cell (VSMC) proliferation is a primary cause of occlusive vascular disease, including atherosclerosis, restenosis after percutaneous interventions, and bypass graft stenosis. Angiogenesis is implicated in the progression of early atheromatous lesions in animal models, but its role in neointimal VSMC proliferation is undefined. Because percutaneous coronary interventions result in induction of periadventitial angiogenesis, we analyzed the role of this process in neointima formation. METHODS AND RESULTS: Local injury to the arterial wall in 2 different animal models induced periadventitial angiogenesis and neointima formation. Application of angiogenesis stimulators vascular endothelial growth factor (VEGF-A165) or a proline/arginine-rich peptide (PR39) to the adventitia of the injured artery induced a marked increase in neointimal thickening beyond that seen with injury alone in both in vivo models. Inhibition of either VEGF (with soluble VEGF receptor 1 [sFlt1]) or fibroblast growth factor (FGF) (with a dominant=negative form of FGF receptor 1 [FGF-R1DN]), respectively, signaling reduced adventitial thickening induced by VEGF and PR39 to the level seen with mechanical arterial injury alone. However, neither inhibitor was effective in preventing neointimal thickening after mechanical injury when administered in the absence of angiogenic growth factor. CONCLUSIONS: Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it.

Angiogenesis Inducing Agents↗
PubMed2000

Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary.

The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

Angiogenesis Inducing Agents↗
PubMed2002

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA.

Angiogenesis is implicated in the pathogenesis of cancer, rheumatoid arthritis, and atherosclerosis and in the treatment of coronary artery and peripheral vascular disease. Here, cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are shown to interfere with angiogenesis. In vivo, the HMG-CoA reductase inhibitor simvastatin dose-dependently inhibited capillary growth in both vascular endothelial growth factor-stimulated chick chorioallantoic membranes and basic fibroblast growth factor-stimulated mouse corneas. In vitro, the development of tubelike structures by human microvascular endothelial cells cultured on 3D collagen gels was inhibited at simvastatin concentrations similar to those found in the serum of patients on therapeutic doses of this agent. HMG-CoA reductase inhibitors interfered with angiogenesis via inhibition of the geranylgeranylation and membrane localization of RhoA. Simvastatin inhibited membrane localization of RhoA with a concentration dependence similar to that for the inhibition of tube formation, whereas geranylgeranyl pyrophosphate, the substrate for the geranylgeranylation of Rho, reversed the effect of simvastatin on tube formation and on the membrane localization of RhoA. Furthermore, tube formation was inhibited by GGTI, a specific inhibitor of the geranylgeranylation of Rho; by C3 exotoxin, which inactivates Rho; and by the adenoviral expression of a dominant-negative RhoA mutant. The expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on tube formation. Finally, HMG-CoA reductase inhibitors inhibited signaling by vascular endothelial growth factor, Akt, and focal adhesion kinase, three RhoA-dependent pathways known to be involved in angiogenesis. This study demonstrates a new relationship between lipid metabolism and angiogenesis and an antiangiogenic effect of HMG-CoA reductase inhibitors with possible important therapeutic implications.

Angiogenesis Inhibitors↗
PubMed2003

Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis.

Patients with multiple myeloma (MM) have increased bone marrow (BM) angiogenesis; however, the proangiogenic properties of myeloma cells and the mechanisms of MM-induced angiogenesis are not completely clarified. The angiopoietin system has been identified as critical in the regulation of vessel formation. In this study we have demonstrated that myeloma cells express several proangiogenic factors, and, in particular, we found that angiopoietin-1 (Ang-1), but not its antagonist Ang-2, was expressed by several human myeloma cell lines (HMCLs) at the mRNA and the protein levels. In a transwell coculture system, we observed that myeloma cells up-regulated the Ang-1 receptor Tie2 in human BM endothelial cells. Moreover, in an experimental model of angiogenesis, the conditioned medium of HMCLs significantly stimulated vessel formation compared with control or vascular endothelial growth factor (VEGF) treatment. The presence of anti-Tie2 blocking antibody completely blunted the proangiogenic effect of XG-6. Finally, our in vitro results were supported by the in vivo finding of Ang-1, but not Ang-2, mRNA and protein expression in purified MM cells obtained from approximately 47% of patients and by high BM angiogenesis in patients with MM positive for Ang-1, suggesting that the angiopoietin system could be involved, at least in part, in MM-induced angiogenesis.

Adult↗
PubMed2004

Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A.

Monocyte chemoattractant protein-1 (MCP-1) has been recognized as an angiogenic chemokine. In the present study, we investigated the detailed mechanism by which MCP-1 induces angiogenesis. We found that MCP-1 up-regulated hypoxia-inducible factor 1 alpha (HIF-1 alpha) gene expression in human aortic endothelial cells (HAECs), which induced vascular endothelial growth factor-A(165) (VEGF-A(165)) expression in the aortic wall and HAECs through activation of p42/44 mitogen-activated protein kinase (MAPK). In vivo angiogenesis assay using chick chorioallantoic membrane (CAM) showed that MCP-1-induced angiogenesis was as potent as that induced by VEGF-A(165) and completely inhibited by a VEGF inhibitor, Flt(2-11). The inhibition of RhoA small G protein did not affect MCP-1-induced VEGF-A(165) production and secretion but completely blocked both MCP-1- and VEGF-A-induced new vessel formation, as determined by CAM assay. These results suggest that MCP-1-induced angiogenesis is composed largely of 2 sequential steps: the induction of VEGF-A gene expression by MCP-1 and the subsequent VEGF-A-induced angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2006

G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism.

There is compelling evidence that circulating angiogenic cells exist that are able to home to sites of vascular injury and stimulate angiogenesis. However, the number of angiogenic cells in the blood is low, limiting their delivery to sites of ischemia. Treatment with certain cytokines may mobilize angiogenic cells into the blood, potentially circumventing this limitation. Herein, we show that treatment with granulocyte colony-stimulating factor (G-CSF) or AMD3100, a novel CXCR4 antagonist, significantly stimulated angiogenesis in a murine model of acute hindlimb ischemia. The kinetics of angiogenic-cell mobilization by these agents appears to be distinct, with more rapid revascularization observed in AMD3100-treated mice. Combination treatment with G-CSF and AMD3100 resulted in the earliest and most complete recovery in blood flow to the ischemic hindlimb. Adoptive transfer of mobilized blood mononuclear cells, while potently stimulating angiogenesis, did not result in the significant incorporation of donor cells into the neoendothelium. Cell-fractionation studies showed that it is the monocyte population in the blood that mediates angiogenesis in this model. Collectively, these data suggest that monocytes mobilized into the blood by G-CSF or AMD3100 stimulate angiogenesis at sites of ischemia through a paracrine mechanism.

Angiogenesis Inducing Agents↗
PubMed2006

Therapeutic options to target angiogenesis in human malignancies.

The critical role of angiogenesis in tumour growth and metastasis is now well established in the literature. Growing tumours stimulate neovascularisation through the secretion of pro-angiogenic growth factors, in particular, basic fibroblast growth factor and VEGF. Several lines of evidence have implicated VEGF in tumourigenesis, and understanding the role of VEGF in tumour angiogenesis has facilitated the development of novel targeting agents that specifically interfere with angiogenesis. Different approaches to disrupting tumour-induced angiogenesis encompass tyrosine kinase inhibitor, monoclonal antibodies, small-molecule inhibitors and transcription inhibitors. However, monoclonal antibody and tyrosine kinase inhibitors are the most advanced drug classes currently being investigated in clinical trials. So far, three anti-VEGF inhibitors, bevacizumab, sunitinib and sorafenib, have been approved for the treatment of solid human malignancies including colorectal cancer, gastrointestinal stromal tumours and renal cell carcinoma. Other antiangiogenic drugs are being investigated in various types of cancer. This review summarises the current literature on the use of these agents to interfere with VEGF, VEGF receptor, the matrix breakdown or other mechanisms involved in angiogenesis.

Angiogenesis Inhibitors↗
PubMed1988

Angiogenesis factors in ocular tissues of normal rabbits on chorioallantoic membrane assay.

Recent studies have shown that angiogenesis-stimulatory factors exist in ocular tissues and play a crucial role in the development of some eye disorders such as diabetic retinopathy. However, there are few reports that studied location of angiogenesis factors in ocular tissues of experimental animals. We studied angiogenesis factors in ocular tissues of normal rabbits by chorioallantoic membrane (CAM) assay. Extracts derived from the retina, iris-ciliary body and optic nerve showed an evident activity of angiogenesis. Retinal extracts at 10 micrograms showed a strong angiogenic activity in 50% of CAMs (p less than 0.01). On the other hand, bovine serum albumin which is heterogeneous protein showed only a slight angiogenic activity at a high concentration (1,000 micrograms). The iris-ciliary body and optic nerve showed also an angiogenic activity as did the retina. Extracts from the heart, liver and serum showed no activity of angiogenesis. Thus, angiogenic activity was strongly present in the ocular tissues, especially in retina of the normal rabbits.

Allantois↗
PubMed2006

Angiogenesis inhibitors: perspectives for medical, surgical and radiation oncology.

In the past decade, many angiogenesis inhibitors have been developed for clinical use in oncology. Surgeons, radiotherapists as well as medical oncologists have been investigating with much effort and enthusiasm the translation of these agents from the preclinical setting into treatment strategies of patients. Recently, for the first time in history, the angiogenesis inhibitor bevacizumab (avastin), a humanized anti-vascular endothelial growth factor (VEGF) antibody, showed a survival benefit of 4.7 months in a phase III clinical trial in patients with advanced colorectal cancer when this agent was given in combination with chemotherapy. At the annual meeting of the American Association of Clinical Oncology 2005, similar results of bevacizumab in lung, breast and ovarian cancer clinical trials have been shown. These landmark studies proofed for the first time in the clinical setting that Dr. Folkman back in 1971 was right by proposing: "in order to stop tumor growth, one should attack its blood supply". Nowadays it seems trivial to propose such a hypothesis, at that time it was a very provocative hypothesis and it took more than 30 years to proof this hypothesis in the clinic. Although one may be excited about this major finding, there is no time to relax. The survival benefit of bevacizumab is only about 4 months. Therefore more potent antiangiogenic agents and more active treatment strategies are urgently warranted. Newer angiogenesis inhibitors that are currently in preclinical or early clinical development have shown in preclinical experiments improved antitumor activities. In addition, combinations of biological agents that interfere in multiple biological pathways in cancer growth including chemotherapy, are of major clinical interest as well. The multimodality approach in which surgeons, radiotherapists and medical oncologists collaborate needs to be explored as well. In a variety of cancer types, like breast colon and lung cancer, these specialists should design multimodality strategies based on current standard treatment in which they incorporate angiogenesis inhibitors in the right time frame of surgery and radiotherapy. In this review we will bring you up to date on the clinical development of angiogenesis inhibitors and we will summarize the multimodality strategies that are under development.

Angiogenesis Inhibitors↗
PubMed2004

Development of new drugs in angiogenesis.

Angiogenesis, the growth of new capillaries from pre-existing vessels, contributes to the development and progression of a variety of physio-pathological conditions. There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. Conversely, therapeutic angiogenesis is an important homeostatic response contributing to limit the damage to ischemic tissues. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e. vascular endothelial growth factor, VEGF; fibroblast growth factor-2, FGF-2), degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Drugs targeting pathologic angiogenesis have been designed to interfere with any of these steps and are currently undergoing evaluation in early clinical studies. Important therapeutic strategies are: suppression of activity and signaling pathways activated by the major angiogenic regulators like VEGF and FGF-2; inhibition of function of alphav-integrins and MMPs; exploitation of endogenous anti-angiogenic molecules like angiostatin and endostatin. The strategy to "silence" endothelium with antiangiogenic drugs to starve tumors, provides a novel approach for cancer treatment. The unique targets of these drugs (endothelium) make them distinct from traditional cytotoxic chemotherapeutic agents. Conversely, gene transfer of angiogenesis inducers is the new approach for therapeutic neovascularization, which is under investigation using a variety of growth factors and a wide array of potential delivery systems, including the application of the gene as naked DNA or by viral vector. The status of pro- and anti-angiogenic therapies is here presented and discussed.

Angiogenesis Inhibitors↗
PubMed2005

Development of angiogenesis inhibitors to vascular endothelial growth factor receptor 2. Current status and future perspective.

Angiogenesis, the recruitment of new blood vessels is a crucial mechanism required for both tumor growth and metastasis. Advances in the understanding of the molecular mechanisms underlying the angiogenesis process have led to the discovery of a variety of pharmaceutical agents with antiangiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical investigation. Decades of investigation suggest that vascular endothelial growth factor (VEGF) and its receptors, particularly VEGF receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in tumor-associated angiogenesis. KDR, therefore, represents a good target for therapeutic intervention. A number of agents designed selectively for targeting KDR are being evaluated in various phases of clinical trials in cancer patients. This manuscript reviews briefly the biology of VEGF family of ligands and receptors and of KDR in particular. The attempts to develop effective KDR antagonists, including small molecules, antibodies and others, for therapeutic purposes are discussed comprehensively with special emphasis on tumor angiogenesis.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Extraction of angiogenesis factor from chronic subdural haematomas. Significance in capsule formation and haematoma growth.

The extraction of angiogenesis factor (AGF) from the contents of chronic subdural haematomas was attempted in order to explain the angiogenesis in the capsule. AGF was extracted from eight patients using the modified Phillip's method, which has previously been used for the extraction of tumour angiogenesis factor. The thickness of the haematoma capsule was measured immediately after removal. The Hounsfield units were evaluated as the average value of three areas in the haematoma on CT scans. Chromatographic separation of the treated contents gave five fractions. The highest activity was observed in the fourth fraction on bioassay by the air sac method. The intensities of AGF activity varied from patient to patient. Although no correlation existed between the degree of AGF activity and thickness of the capsule, a positive correlation was seen between the activity and the density of the contents as indicated by Hounsfield's units on a CT scan. This may indicate the existence of a sequence of cause and effect between increase in the AGF activity and haemorrhage in the capsule of the haematoma. AGF activity increases after haemorrhage in the haematoma capsule, leading to acceleration of angiogenesis in the capsule, which promotes the haemorrhagic cause in the haematoma. Thus, a vicious circle between AGF in the haematoma, angiogenesis in the capsule and haemorrhage in the haematoma is established. It is considered that this gives rise to growth of the haematoma.

Adult↗
PubMedDate not supplied

Angiogenesis in acute and chronic leukemias.

Angiogenesis plays a key role in the growth of solid tumors. More recently, accumulating evidence has linked angiogenesis to the pathophysiology of leukemias. Different investigators have shown evidence of increased angiogenesis in the bone marrows of patients with acute and chronic leukemias. Elevated levels of angiogenic factors have also been reported in leukemic patients. A potential role for VEGF as an autocrine growth factor in AML has been suggested. Studies on the role of angiogenesis and VEGF as prognostic factors in leukemia require confirmation. The role of angiogenesis inhibitors in the treatment of leukemia is currently under investigation.

Acute Disease↗
PubMed2000

The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors.

Angiogenesis, or the formation of new blood vessels from preexisting vasculature, plays a major role in tumor growth and metastasis formation. Therefore, inhibiting tumor angiogenesis may be a promising therapeutic strategy. Paracrine stimuli from tumor cells are the main promoters of angiogenesis. They activate endothelial cells to proliferate and migrate, subsequently resulting in new tube formation and blood flow. This complex process involves numerous biological activities. Vascular endothelial growth factor (VEGF) is a potent and specific angiogenic factor. Originally identified for its ability to induce vascular permeability and stimulate endothelial cell growth, VEGF is now known to be a key requirement for tumor growth. Currently, three high-affinity tyrosine kinase receptors for VEGF have been identified, of which VEGF receptor (VEGFR)-Flk-1/KDR (VEGFR-2) is exclusively expressed in vascular endothelial cells. Because the VEGFR-2 system is a dominant signal-transduction pathway in regulating tumor angiogenesis, specific inhibitors of this pathway inhibit metastases, microvessel formation, and tumor-cell proliferation. Induction of apoptosis in tumor cells and endothelial cells has also been observed. The clinical importance of VEGF for tumor growth is supported by the fact that most tumors produce VEGF and that the inhibition of VEGF-induced angiogenesis significantly inhibits tumor growth in vivo. In this review, we discuss the biologic role of VEGF and the therapeutic options for inhibiting VEGF in cancer patients.

Angiogenesis Inhibitors↗