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At least 19 recordsLinked to original sources
PubMed2002

Anti-angiogenic agents for the treatment of brain tumors.

It is accepted that novel therapeutic approaches are needed for the majority of patients with malignant brain tumors. The vascularity of many primary brain tumors and the encouraging preclinical studies suggest that antiangiogenic agents have the potential to become an important component of multimodality treatment of patients with brain tumors. The understanding of the biology of angiogenesis is improving rapidly, offering the hope for more specific vascular targeting of brain tumor neovasculature. Neuroimaging techniques evaluating the angiogenic process and the impact of antiangiogenic agents will be an important tool for the rapid development of these novel therapeutic agents.

Angiogenesis Inducing Agents↗
PubMed2001

Angiogenesis: regulators and clinical applications.

Angiogenesis is a fundamental process in reproduction and wound healing. Under these conditions, neovascularization is tightly regulated. Unregulated angiogenesis may lead to several angiogenic diseases and is thought to be indispensable for solid tumor growth and metastasis. The construction of a vascular network requires different sequential steps including the release of proteases from "activated" endothelial cells with subsequent degradation of the basement membrane surrounding the existing vessel, migration of endothelial cells into the interstitial space, endothelial cell proliferation, and differentiation into mature blood vessels. These processes are mediated by a wide range of angiogenic inducers, including growth factors, chemokines, angiogenic enzymes, endothelial specific receptors, and adhesion molecules. Finally, when sufficient neovascularization has occurred, angiogenic factors are down-regulated or the local concentration of inhibitors increases. As a result, the endothelial cells become quiescent, and the vessels remain or regress if no longer needed. Thus, angiogenesis requires many interactions that must be tightly regulated in a spatial and temporal manner. Each of these processes presents possible targets for therapeutic intervention. Synthetic inhibitors of cell invasion (marimastat, Neovastat, AG-3340), adhesion (Vitaxin), or proliferation (TNP-470, thalidomide, Combretastatin A-4), or compounds that interfere with angiogenic growth factors (interferon-alpha, suramin, and analogues) or their receptors (SU6668, SU5416), as well as endogenous inhibitors of angiogenesis (endostatin, interleukin-12) are being evaluated in clinical trials against a variety of solid tumors. As basic knowledge about the control of angiogenesis and its role in tumor growth and metastasis increases, it may be possible in the future to develop specific anti-angiogenic agents that offer a potential therapy for cancer and angiogenic diseases.

Angiogenesis Inducing Agents↗
PubMed2004

Surgery and angiogenesis.

Surgery may be regarded as an angiogenesis-inducing condition since it evokes the release of many angiogenic factors. Regarding the mechanistic overlap between tumor-associated neovascularisation and (physiological) angiogenesis in response to injury and hypoxia, surgery may promote the uncontrolled growth of residual dormant tumor cells. With the advent of anti-angiogenic agents, surgeons will be faced with more patients undergoing surgery for primary and secondary tumors under anti-angiogenic treatment. This could present problems with regard to angiogenesis-dependent phenomena such as wound repair, healing of intestinal anastomoses and liver regeneration. In this review we will discuss these matters from a biomedical and clinical point of view.

Angiogenesis Inducing Agents↗
PubMed2002

Angiogenesis in bladder cancer--prognostic marker and target for future therapy.

Angiogenesis is the process by which tumours induce a blood supply, crucial for growth and metastasis. Evidence for its role in bladder carcinogenesis, its usefulness as a marker of patient prognosis, and potential anti-angiogenic therapies for future development are discussed in this chapter.

Angiogenesis Inducing Agents↗
PubMedDate not supplied

[Angiogenesis and anti-angiogenesis in human neoplasms. Recent developments and the therapeutic prospects].

Angiogenesis entails new vessel formation from preexisting vessels. It follows vasculogenesis during embryo development. In post-natal life, it occurs both in physiological conditions (wound repair and cyclically in the female genital system) and pathological conditions such as tumors. Several sequential steps are involved, including basement membrane degradation by proteolytic enzymes secreted by the endothelial cells, chemotaxis toward the stimulus and proliferation of these cells, canalization, branching and formation of vascular loops, stabilization and functional maturation of neovessels following perivascular apposition of pericytes and smooth muscle cells, and neosynthesis of basement membrane constituents. Tumor angiogenesis is regulated by several factors, mainly growth factors for the endothelial cells secreted by both the tumor and host inflammatory cells, and mobilized from extracellular matrix stores by proteases secreted by tumor cells. Regulatory factors also include the extracellular matrix components and endothelial cell integrins, hypoxia, oncogenes and tumor suppressor genes. Angiogenesis is mandatory to the process of tumor progression (growth, invasion and metastasis), since it conveys oxygen and metabolites, whereas endothelial cells secrete growth factors for tumor cells and a variety of proteinases which facilitate invasion and increase opportunities for tumor cells to enter the circulation. We present our results concerning the relationship between angiogenesis and progression in patients with melanoma, multiple myeloma, B-cell non-Hodgkin's lymphomas and mycosis fungoides. Lastly, it is becoming increasingly evident that agents interfering with blood vessel formation also interfere with tumor progression. These include antagonists of angiogenic growth factors, angiogenic receptors, endothelial cell integrins, and proteolytic enzymes, as well as non-specific toxic agents for vessels and low-dose chemotherapeutic agents. Their recent applications in preclinical models and in neoplastic patients are reviewed.

Angiogenesis Inducing Agents↗
PubMed2002

Antiangiogenic effects of a protein kinase Cbeta-selective small molecule.

BACKGROUND: Protein kinase C frequently plays a central role in the intracellular signal transduction of growth factors and cytokines. METHODS: The acyclic bisindolylmaleimide 317615 x 2HCl was identified as a potent selective inhibitor of protein kinase Cbeta. The compound 317615 x 2HCl was tested in culture and in vivo in the rat corneal micropocket and in the SW2 small-cell lung carcinoma human tumor xenograft. RESULTS: In cell culture, 317615 x 2HCl was a more potent inhibitor of VEGF-stimulated HUVEC proliferation (IC50 150 nM, 72 h) than of human SW2 small-cell lung carcinoma cell proliferation (IC50 3.5 microM, 72 h). When administered orally twice daily for 10 days, the compound 317615 x 2HCl markedly decreased the neoangiogenesis induced by VEGF or bFGF in the rat corneal micropocket assay. To assess antitumor efficacy, 317615 x 2HCl was administered orally twice daily to nude mice bearing SW2 xenograft tumors on days 14 through 30 after tumor implantation. The number of countable intratumoral vessels was decreased in a dose-dependent manner reaching as low as one-quarter the number in the control tumors. The decrease in intratumoral vessels was paralleled by increases in tumor growth delay. Treatment of the tumor-bearing animals with paclitaxel or carboplatin followed by treatment with 317615 x 2HCl resulted in a 2.5- to 3.0-fold increase in tumor growth delay compared with the standard chemotherapeutic agents alone. CONCLUSIONS: 317615 x 2HCl represents a new approach to antiangiogenic therapy in cancer-blocking multiple growth factor signaling pathways in endothelial cells with a single agent. 317615 x HCl is in early clinical testing.

Angiogenesis Inducing Agents↗
PubMed2007

Molecular imaging of angiogenesis.

Angiogenesis (the growth of new blood vessels) is a complex multistep process that involves multiple cell types, numerous growth factors, and complex regulatory checks and balances. Tight control of vascular remodeling evolved to ensure stability of the vasculature while maintaining the body's ability to rapidly mount an angiogenic response requiring a high degree of plasticity. Angiogenesis is critical not only for physiological development, but also for the progression of pathologies, and is thus a target for therapeutic intervention. The importance of the process coupled with the ease of access for delivery of contrast agents makes the vasculature at large, and angiogenesis in particular, a favorable target of functional and molecular imaging. Recent developments in molecular imaging tools have expanded our views to encompass many components of the process. Functional imaging of blood volume, vessel permeability, and vasoreactivity is complemented by novel contrast agents that reveal specific targets on endothelial cells. Methods have been developed to label vascular cells so as to track their recruitment to sites of angiogenesis, and new "smart" contrast agents have been designed to reveal the activity of enzymatic reactions in altering the extracellular matrix (ECM) during angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2006

Role of angiogenesis in chronic lymphocytic leukemia.

Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

Angiogenesis Inducing Agents↗
PubMedDate not supplied

Vascular endothelial growth factor and DPC4 predict adjuvant therapy outcomes in resected pancreatic cancer.

Angiogenesis is important for pancreatic cancer progression, but its role in predicting response to therapy is not known. We investigated the association of various angiogenic factors and intratumoral microvessel density (IMD) with adjuvant therapy and survival in resected pancreatic cancer. Tissue cores from a multi-institutional retrospective series of resected patients were used to build a pancreatic cancer tissue microarray. Vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF), CD31 (for IMD), and DPC4 expression were determined using immunohistochemistry. Expression of VEGF and PD-ECGF, both proangiogenic factors, was observed in 70 (56%) and 75 (59%) of 124 tumors, respectively. Expression of DPC4, an angiogenesis inhibitor, was observed in 59 of 124 (48%) tumors. VEGF expression correlated significantly with increased IMD (P=.03), as did loss of antiangiogenic DPC4 (P=.05). PD-ECGF expression did not correlate with IMD. Use of adjuvant therapy was associated with increased survival in patients with VEGF-positive tumors (18.8 [treated] versus 11.2 [untreated] months; hazard ratio [HR]=0.38, 95% confidence interval [CI], 0.19-0.76; P=.005), but not in patients with VEGF-negative tumors. Similarly, improved survival was observed in patients with high IMD (16.3 [treated] versus 11.2 [untreated] months; HR=0.44, 95% CI, 0.23-0.87; P=.02) and in patients with loss of DPC4 (20.3 [treated] versus 11.2 [untreated] months; HR=0.31, 95% CI, 0.14-0.67; P=.002), but not in those with low IMD or normal DPC4 expression. VEGF (stimulator) and DPC4 (inhibitor) are important regulators of pancreatic tumor angiogenesis and predictive of benefit from adjuvant therapy. Adjuvant therapy may have both antiangiogenic and cytotoxic effects. Addition of anti-VEGF agents to adjuvant regimens may further improve outcomes.

Age Factors↗
PubMed2002

Angiogenesis in non-small cell lung cancer. A new target for therapy.

Non-small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development. Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established. We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.

Angiogenesis Inducing Agents↗
PubMed2002

Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction.

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

Angiogenesis Inducing Agents↗
PubMed2002

Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis.

Angiopoietin-1 is an important regulator of endothelial cell survival. Angiopoietin-1 also reduces vascular permeability mediated by vascular endothelial growth factor. The effects of angiopoietin-1 on tumour growth and angiogenesis are controversial. We hypothesised that angiopoietin-1 would decrease tumour growth and ascites formation in peritoneal carcinomatosis. Human colon cancer cells (KM12L4) were transfected with vector (pcDNA) alone (control) or vector containing angiopoietin-1 and injected into the peritoneal cavities of mice. After 30 days, the following parameters were measured: number of peritoneal nodules, ascites volume, and diameter of the largest tumour. Effects of angiopoietin-1 on vascular permeability were investigated using an intradermal Miles assay with conditioned media from transfected cells. Seven of the nine mice in the pcDNA group developed ascites (1.3+/-0.5 ml (mean+/-s.e.m.)), whereas no ascites was detectable in the angiopoietin-1 group (0 out of 10) (P<0.01). Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours. Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05). Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer.

Angiogenesis Inducing Agents↗
PubMed2002

Issues and challenges for antiangiogenic therapies.

Angiogenesis is defined as the growth and proliferation of blood vessels from the existing vasculature, allowing a developing tissue to obtain the nutrients necessary to maintain growth. This fundamental mechanism underlies the processes of reproduction, development and repair and occurs in both normal and tumor tissues. Since this process is confined to rapidly growing tissues, and is quiescent in normal tissues, it was hypothesized by Folkman that any therapeutic intervention that inhibited angiogenesis would be relatively specific to tumors, sparing normal tissue. The mechanisms by which tumors induce angiogenesis are complex. Tumors rapidly outgrow the capacity of the vasculature in their host tissue to provide nutrition and oxygenation, and are inherently hypoxic. In response to hypoxia, they produce a number of potent protein-mediators that stimulate the growth of new blood vessels. These angiogenic factors are not specific to tumors - they are produced by all tissues in response to hypoxia. Many of the mechanisms have been elucidated at a molecular level, and a number of ligands, receptors and signal-transduction pathways defined. Many of these represent potential targets for the development of novel therapeutic agents. Several drug candidates that target angiogenic mechanisms are currently being evaluated in breast cancer. The ultimate goal of all such development is to improve disease outcome, and to augment currently available therapies. However, the evaluation of these drug candidates in clinical studies is complex and requires a fundamental re-appraisal of conventional clinical trial methodology and the application of advanced bioscientific technology to facilitate understanding of the complex pharmacology that they may produce.

Angiogenesis Inducing Agents↗
PubMed2001

Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors.

In postnatal tissues, angiogenesis occurs in nontumoral conditions on appropriate stimuli. In the nervous tissue, hypoxia, neural graft, increased neural function, and synaptic activity are associated with neoangiogenesis. We have investigated the occurrence of neoangiogenesis in the superior cervical ganglia (scg) of newborn rats treated for 8--21 days with 6-hydroxy-dopamine (6-OHDA), nerve growth factor (NGF), or 6-OHDA + NGF. The two latter treatments induced a significant increase in scg size. However, the increase after combined treatment far exceeded that of NGF alone. Similarly, histological and histochemical analysis revealed neuronal hypertrophy and endothelial cell hyperplasia associated with stromal hypertrophy (as described by laminin immunostaining) and increased vascular bed (as revealed by platelet/endothelial cell adhesion molecule-1 immunostaining) in 6-OHDA + NGF-treated pups. NGF, either alone or associated with 6-OHDA, also induced a significant up-regulation of NADPH diaphorase, neuronal nitric oxide synthase, and vascular endothelial growth factor expression in scg neurons. The present investigation suggests that the increase of scg size induced by NGF and 6-OHDA + NGF is associated with neoangiogenesis, and that the induction of vasoactive and angiogenic factors in neurons represents a further and previously undisclosed effect of NGF.

Adrenergic Agents↗
PubMed2003

Angiotherapeutics from natural products: from bench to clinics?

Angiogenesis offers an enormous potentials for therapeutic intervention of many disorders afflicting mankind at present. With the identification of the major molecular players involved in the sequence of events leading to the formation of new blood vessels from pre-existing capillaries, inhibition or induction of the process may now be regulated. Bioactive compounds from natural sources may be used as regulatory agents. Inhibition of angiogenesis can control diseases characterized with excessive blood vessel growth like cancer, arthritis, psoriasis and diabetes retinopathy. Stimulation of angiogenesis would be favorable in the treatment of ischemic disorders and tissue engineering. An increasing number of bioactive compounds from natural sources and whose chemical structures have already been elucidated are reported as either potential inhibitors or inducers of angiogenesis. Drug development from natural products is a fast-emerging field that needs to be supported to provide people with more readily available and affordable healthcare.

Angiogenesis Inducing Agents↗
PubMed2006

Isolated pancreatic islets in three-dimensional matrices are responsive to stimulators and inhibitors of angiogenesis.

The formation of a new microvasculature is essential for the long-term survival and function of the islet graft. In this study we examined endothelium of isolated pancreatic islets by stimulation with growth factors, different culture conditions, and genetic modification. We also inspected the effect of immunosuppressives used in human transplantation on angiogenesis. Isolated islets were embedded in a three-dimensional fibrin or Matrigel matrix. The effect of hyperglycemia, hypoxia, and the addition of VEGF and bFGF was investigated. We exposed islets from transgenic mice expressing the VEGF gene (RIP1VEGF-A) to high glucose (16.7 mmol/L) medium and tested the immunosuppressive agents rapamycin (100 ng/ml) and FK506 (100 ng/ml). To quantify angiogenesis the percentage of sprouting islets was determined. New endothelial capillary-like structures protruded from isolated pancreatic islets. Addition of VEGF to the islets and transgenic RIP-VEGF islets showed a two- to threefold increase of sprouting islets compared to control. Hypoxic culture conditions stimulated angiogenesis, resulting in a twofold increase of capillary sprouting. Rapamycin and FK506 proved to be potent inhibitors of angiogenesis in this system, because a decrease of sprouting islets of more than 20% by both agents was observed. Isolated pancreatic islets are capable of forming new capillary structures and are susceptible to pro- and antiangiogenic stimuli.

Angiogenesis Inducing Agents↗
PubMed2005

Angiogenesis in rheumatoid arthritis.

Endothelial cells lining the lumina of blood vessels are involved in leukocyte extravasation underlying inflammatory states, such as rheumatoid arthritis (RA). New vessel formation, termed angiogenesis, is also crucial for leukocyte extravasation during inflammatory synovitis. The outcome of neovascularization in the RA synovium is highly dependent on the balance or imbalance between angiogenic mediators and inhibitors. There have been several attempts to therapeutically interfere with the cellular and molecular mechanisms underlying RA-associated neovascularization. Most studies have been performed using animal models of arthritis. In addition, a limited number of human clinical trials gave promising results. In this review, authors summarize some relevant information on those angiogenic and angiostatic agents, which have also been studied in context with RA. In addition, further perspectives of anti-angiogenic therapy in arthritis are also discussed. Specific targeting of angiogenesis may be useful in the future management of various inflammatory, as well as malignant, diseases.

Angiogenesis Inducing Agents↗