Angiostatic Agents Research Articles

The extracellular adherence protein fromStaphylococcus aureusabrogates angiogenic responses of endothelial cells by blocking Ras activation

The extracellular adherence protein (Eap), a broad-spectrum adhesin secreted by Staphylococcus aureus, was previously shown to curb acute inflammatory responses, presumably through its binding to endothelial cell (EC) ICAM-1. Examining the effect of Eap on endothelial function in more detail, we here show that, in addition, Eap functions as a potent angiostatic agent. Concomitant treatment of EC with purified Eap resulted in the complete blockage of the mitogenic and sprouting responses elicited by vascular endothelial growth factor (VEGF)165 or basic fibroblast growth factor (bFGF). Moreover, the induction of tissue factor and decay-accelerating factor were repressed by Eap, as determined by qRT-polymerase chain reaction (qRT-PCR), with a corresponding reduction in Egr-1 protein up-regulation seen. This angiostatic activity was accompanied by a corresponding inhibition in ERK1/2 phosphorylation, while activation of p38 was not affected. Inhibition occurred downstream of tyrosine kinase receptor activation, as comparable effects were seen on TPA-induced ERK1/2 phosphorylation. Similar to previously described angiostatic agents like angiopoietin-1 or the 16-kDa prolactin fragment, Eap blockage of the Ras/Raf/MEK/ERK cascade was localized by pull-down assay at the level of Ras activation. Eap's combined anti-inflammatory and antiangiogenic properties render this bacterial protein not only an important virulence factor during S. aureus infection but open new perspectives for therapeutic applications in pathological neovascularization.

Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature

AbstractCrucial to designing angiostatic and vascular targeting agents is the identification of target molecules. Because angiogenesis is not limited to pathologic conditions, careful evaluation of putative therapeutic targets is warranted to prevent adverse effects associated with impaired physiologic angiogenesis. To identify tumor-specific angiogenesis markers, we compared transcriptional profiles of angiogenic endothelial cells isolated from malignant and nonmalignant tissues with those of resting endothelial cells. We identified 17 genes that showed specific overexpression in tumor endothelium but not in angiogenic endothelium of normal tissues, creating a therapeutic window for tumor vasculature-specific targeting. Antibody targeting of 4 cell-surface–expressed or secreted products (vimentin, CD59, HMGB1, IGFBP7) inhibited angiogenesis in vitro and in vivo. Finally, targeting endothelial vimentin in a mouse tumor model significantly inhibited tumor growth and reduced microvessel density. Our results demonstrate the usefulness of the identification and subsequent targeting of specific tumor endothelial markers for anticancer therapy.

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis

The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.

Fibulins 3 and 5 Antagonize Tumor Angiogenesis In vivo

Lethal tumor growth and progression cannot occur without angiogenesis, which facilitates cancer cell proliferation, survival, and dissemination. Fibulins (FBLN) 5 and 3 are widely expressed extracellular matrix proteins that regulate cell proliferation in a context-specific manner. Reduced FBLN-5 expression has been associated with cancer formation and progression in humans, whereas its constitutive expression antagonizes endothelial cell angiogenic sprouting in vitro. Thus, FBLN-5 may suppress tumorigenesis by preventing tumor angiogenesis. FBLN-3 is homologous to FBLN-5 and expressed in endothelial cells, yet its role in tumorigenesis and angiogenesis is unknown. We find FBLN-3 expression to be altered in some human tumors and that its constitutive expression in endothelial cells inhibited their proliferation, invasion, and angiogenic sprouting, as well as their response to vascular endothelial growth factor as measured by p38 mitogen-activated protein kinase activation. In endothelial cells, both FBLNs (a) reduced angiogenic sprouting stimulated by basic fibroblast growth factor (bFGF); (b) inhibited matrix metalloproteinase expression and activity; and (c) stimulated tissue inhibitor of metalloproteinase expression. More importantly, both FBLNs prevented angiogenesis and vessel infiltration into bFGF-supplemented Matrigel plugs implanted in genetically normal mice, as well as decreased the growth and blood vessel density in tumors produced by MCA102 fibrosarcoma cells implanted s.c. into syngeneic mice. Our findings establish FBLN-3 and FBLN-5 as novel angiostatic agents capable of reducing tumor angiogenesis and, consequently, tumor growth in vivo and suggest that these angiostatic activities may one day be exploited to combat tumor angiogenesis and metastasis in cancer patients.

Plasminogen Kringle 5–Engineered Glioma Cells Block Migration of Tumor-Associated Macrophages and Suppress Tumor Vascularization and Progression

Angiostatin, a well-characterized angiostatic agent, is a proteolytic cleavage product of human plasminogen encompassing the first four kringle structures. The fifth kringle domain (K5) of human plasminogen is distinct from angiostatin and has been shown, on its own, to act as a potent endothelial cell inhibitor. We propose that tumor-targeted K5 cDNA expression may act as an effective therapeutic intervention as part of a cancer gene therapy strategy. In this study, we provide evidence that eukaryotically expressed His-tagged human K5 cDNA (hK5His) is exported extracellularly and maintains predicted disulfide bridging conformation in solution. Functionally, hK5His protein produced by retrovirally engineered human U87MG glioma cells suppresses in vitro migration of both human umbilical vein endothelial cells and human macrophages. Subcutaneous implantation of Matrigel-embedded hK5His-producing glioma cells in nonobese diabetic/severe combined immunodeficient mice reveals that hK5His induces a marked reduction in blood vessel formation and significantly suppresses the recruitment of tumor-infiltrating CD45+ Mac3+ Gr1- macrophages. Therapeutically, we show in a nude mouse orthotopic brain cancer model that tumor-targeted K5 expression is capable of effectively suppressing glioma growth and promotes significant long-term survival (>120 days) of test animals. These data suggest that plasminogen K5 acts as a novel two-pronged anticancer agent, mediating its inhibitory effect via its action on host-derived endothelial cells and tumor-associated macrophages, resulting in a potent, clinically relevant antitumor effect.

Expression and Function of Laminins in the Embryonic and Mature Vasculature

Endothelial cells of the blood and lymphatic vasculature are polarized cells with luminal surfaces specialized to interact with inflammatory cells upon the appropriate stimulation; they contain specialized transcellular transport systems, and their basal surfaces are attached to an extracellular basement membrane. In adult tissues the basement membrane forms a continuous sleeve around the endothelial tubes, and the interaction of endothelial cells with basement membrane components plays an important role in the maintenance of vessel wall integrity. During development, the basement membrane of endothelium provides distinct spatial and molecular information that influences endothelial cell proliferation, migration, and differentiation/maturation. Microvascular endothelium matures into phenotypically distinct types: continuous, fenestrated, and discontinuous, which also differ in their permeability properties. Development of these morphological and physiological differences is thought to be controlled by both soluble factors in the organ or tissue environment and by cell-cell and cell-matrix interactions. Basement membranes of endothelium, like those of other tissues, are composed of laminins, type IV collagens, heparan sulfate proteoglycans, and nidogens. However, isoforms of all four classes of molecules exist, which combine to form structurally and functionally distinct basement membranes. The endothelial cell basement membranes have been shown to be unique with respect to their laminin isoform composition. Laminins are a family of glycoprotein heterotrimers composed of an alpha, beta, and gamma chain. To date, 5alpha, 4beta, and 3gamma laminin chains have been identified that can combine to form 15 different isoforms. The laminin alpha-chains are considered to be the functionally important portion of the heterotrimers, as they exhibit tissue-specific distribution patterns and contain the major cell interaction sites. Vascular endothelium expresses only two laminin isoforms, and their expression varies depending on the developmental stage, vessel type, and the activation state of the endothelium. Laminin 8 (composed of laminin alpha4, beta1, and gamma1 chains) is expressed by all endothelial cells regardless of their stage of development, and its expression is strongly upregulated by cytokines and growth factors that play a role in inflammatory events. Laminin 10 (composed of laminin alpha5, beta1, and gamma1 chains) is detectable primarily in endothelial cell basement membranes of capillaries and venules commencing 3-4 wk after birth. In contrast to laminin 8, endothelial cell expression of laminin 10 is upregulated only by strong proinflammatory signals and, in addition, angiostatic agents such as progesterone. Other extracellular matrix molecules, such as BM40 (also known as SPARC/osteonectin), thrombospondins 1 and 2, fibronectin, nidogens 1 and 2, and collagen types VIII, XV, and XVIII, are also differentially expressed by endothelium, varying with the endothelium type and/or pathophysiological state. The data argue for a dynamic endothelial cell extracellular matrix that presents different molecular information depending on the type of endothelium and/or physiological situation. This review outlines the unique structural and functional features of vascular basement membranes, with focus on the endothelium and the laminin family of glycoproteins.

Endothelial Cells in Inflammation and Angiogenesis

Endothelial cells are involved in leukocyte extravasation underlying inflammation. A number of adhesion molecules play a role in leukocyte-endothelial interactions. New vessel formation, termed angiogenesis, is also crucial for leukocyte extravasation. The outcome of neovascularization 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, such as leukocyte-endothelial cell adhesion and angiogenesis. Most studies have been performed using animal models of various types of inflammation, such as arthritis. In addition, a very limited number of human clinical trials gave promising results. In this review, authors summarize the most relevant information on adhesion molecules, as well as angiogenic and angiostatic agents. In addition, further perspectives of anti-adhesive and anti-angiogenic therapy are also discussed. Specific targeting of pathological endothelial function including adhesion and angiogenesis, may be useful for the future management of various inflammatory diseases.

312. Human Plasminogen Kringle 5-Engineered Murine Mammary Cancer Cells Arrest Tumor Growth and Promote Long-Term Survival

Objective: Neoangiogenesis has been strongly correlated with aggressive breast tumor growth and metastasis. However, since tumor-associated neovasculature is not of malignant origin, it retains the ability to respond physiologically to growth arrest signals and is the proposed basis for breast tumor regression in vivo. The fifth kringle (K5) domain of human plasminogen is distinct from angiostatin (K1-4), and has been shown -on its own- to act as a potent suppressor of angiogenesis. We propose that the K5 domain may serve as a potent angiostatic agent and that it may act as a useful therapeutic transgene within a breast cancer gene therapy strategy. To test this hypothesis, we have developed a K5-expressing retroviral vector, gene-modified murine DA3 mammary cells to produce soluble human K5 protein and characterized the anti-tumor potency of the de novo produced K5 peptide in vivo.

Angiostatic agents prevent the development of endometriosis-like lesions in the chicken chorioallantoic membrane

A prospective study was performed to determine the effects of the angiostatic compounds anti-hVEGF antibody, TNP-470, endostatin, and anginex on the vascularization and on endometriosis-like lesion formation in the chicken chorioallantoic membrane model. Endometriosis-like lesion formation was significantly impaired after treatment with angiostatic agents, which was associated with decreased vessel densities in the surrounding chorioallantoic membrane and more necrosis in the endometriosis-like lesions.

Le PPAR gamma : une nouvelle cible pharmacologique contre la néovascularisation rétinienne et choroïdienne

PPARg (peroxisome proliferator-activated receptor gamma) is a nuclear receptor that regulates the transcription of numerous genes involved in the differentiation, proliferation and apoptosis of various cell types. It was initially discovered in adipocytes as a differentiation agent, then was characterized in vascular endothelium and recently in choroidal and retinal endothelial cells. Agonists that bind to PPARgamma and stimulate its transcriptional activity are endogenous lipids such as lysophosphatidic acid and 15-d-PGJ2 as well as the synthetic pharmacological compounds, thiazolidinediones, used for treating type 2 diabetes. These ligands prevent choroidal and retinal neovascularization in several experimental animal models, notably through the inhibition of vascular endothelial growth factor (VEGF) receptor expression. Because of the high affinity and the low molecular weight of agonists, suitable for good bioavailability, PPARgamma could potentially be a novel pharmacological target of angiostatic agents, particularly useful to treat age-related macular degeneration and diabetic retinopathy.

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.

Ghrelin inhibits FGF-2-mediated angiogenesis in vitro and in vivo

Recent evidence indicates that ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is highly expressed in the cardiovascular system, and in this study we addressed the possibility that ghrelin may affect angiogenesis in vitro and in vivo. Reverse transcription-polymerase chain reaction showed that human umbilical vein endothelial cells (HUVECs) express ghrelin and GHS-R mRNAs. Ghrelin inhibited FGF-2-induced proliferation of HUVECs cultured in vitro, the maximal effective concentration being 10 −8 M, and this effect was annulled by the GHS-R antagonist d-Lys 3-growth hormone releasing peptide-6. FGF-2 stimulated HUVEC cultured on Matrigel to form capillary-like structures, and ghrelin (10 −8 M) suppressed this effect. In the chick embryo chorioallantoic membrane in vivo assay, FGF-2 induced a strong angiogenic response, which was counteracted by ghrelin (500 ng). Taken together, these findings suggest that ghrelin acts as an angiostatic molecule and indicate that its activity is comparable to that of a well-known angiostatic agent, i.e., vinblastine. The antiangiogenic activity of ghrelin deserves further investigations, alone or together with other antiangiogenic agents, for the treatment of pathological conditions characterized by enhanced angiogenesis.

972. Gene-Modified Human Glioma Cells Producing Soluble Human Plasminogen Kringle 5 Peptide Suppress Brain Tumor Progression

Objective: Glioblastoma multiforme is one of the most highly vascularized tumors in humans. Therefore, the development of a potent anti-angiogenic gene therapy strategy for brain cancer represents an attractive alternative to existing therapeutic interventions and circumvents the pitfalls associated with direct recombinant anti-angiogenic protein delivery. Amongst the known human angiogenic inhibitors, the fifth kringle (K5) of plasminogen has been found to enhance the angiostatic potency of angiostatin, a cleavage product of human plasminogen. We propose that the K5 domain may serve as a potent angiostatic agent on its own and that it may act as a useful therapeutic transgene within a cancer gene therapy strategy. To test this hypothesis, we have developed a K5-expressing retroviral vector and have characterized the angiostatic activity of the de novo produced K5 peptide in vitro and tested its efficacy in vivo using an orthotopic brain cancer model. Methods: To assess the endothelial cell inhibitory properties of retrovector-generated K5 peptide, the 363bp human plasminogen K5 domain cDNA was His-tagged and cloned into a bicistronic retroviral vector comprising the enhanced green fluorescent protein reporter gene. Upon transfection of K5 retrovector plasmid into 293GPG retroviral packaging cells, single clones were drug selected and characterized. Kringle 5 retroparticles were then used to transduce U87 human glioma cells, whereby single clones were isolated and characterized. Results: Southern blot analysis on K5 transduced U87 glioma cells using a GFP cDNA-specific probe suggests unrearrangement upon integration into the genome of transduced glioma cells. Anti-His immunoblot analysis on conditioned culture media collected from K5 transduced U87 glioma cells revealed a major 18kDa protein consistent with the predicted MW of soluble K5, which was capable of inhibiting HUVEC migration up to 75±3% (p<0.0005) and disrupting capillary tube formation. Upon intracerebral implantation of U87-GFP and U87-K5 glioma cells in nude mice, hematoxylin and eosin-stained brain tissue sections reveal that U87-K5 implanted mice possess significantly reduced tumor volumes as compared to the mock implanted mice 32 days post-implantation (Figure 1).

Experimental therapy of malignant mesothelioma: new perspectives from anti-angiogenic treatments

We reviewed the published literature of clinical studies in malignant mesothelioma (MM), including phase II as well as older single-agent and combination chemotherapy trials with more than 15 patients. While response rates exceeding 30% have been achieved with established cytotoxic drugs in MM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the anti-metabolites (i.e. pemetrexed) that produced response rates of up to 45% in combination with platinum compounds. Moreover, agents targeting novel proliferative and survival pathways in MM are developed to improve treatment outcomes. Here, we focused on the role of several angiogenic growth factors in MM biology and the data of MM-oriented studies on angiostatic agents tested in a phase I–II trial. It seems likely that no single treatment modality will be effective by itself. Studies that use combinations of the newer agents, including angiostatic drugs, with chemotherapy, should be conducted.

148 2‐Methoxyestradiol, an Endogenous Estrogen Metabolite, Regulates Apoptosis in Skin Microvascular Endothelial Cells

Programmed cell death or apoptosis regulates the sequence of cellular events that are involved in the wound healing process. Understanding the mechanisms controlling apoptosis during tissue repair may lead to the development of modalities to improve healing and reduce scarring. 2‐Methoxyestradiol (2ME), a naturally occurring metabolite of 17‐ estradiol, has recently emerged as a promising anti‐proliferative and angiostatic agent with minimal toxicity at pharmacological doses. However, the mechanism by which 2ME induces its anti‐proliferative and apoptotic activities is uncertain, and its physiological function remains to be determined. In the present study we examined the effects of physiological and pharmacological concentrations 2ME in human skin microvascular endothelial cells.Our findings show that 2ME rapidly activates JNK and p38 MAP kinase pathways at both physiological and supraphysiological levels. Our results indicate that the rapid activation of p38 and JNK are not required for 2ME‐induced inhibition of DNA synthesis, caspase‐3 activation, or cell cycle arrest, and thus apoptosis, in microvascular endothelial cells. On the contrary, our results suggest that rapid activation of JNK and p38 MAP kinases likely mediates an early pro‐survival response to 2ME. The fine regulation of survival versus apoptotic signals may contribute to the ability of 2ME to elicit its effects in endothelial cells. Since endothelial cells play an essential role during wound healing, identification 2ME as a potent regulator of endothelial cell proliferation and function warrants further studies of its therapeutic potential as an agent to manipulate wound repair events.

Antiangiogenesis therapy for endometriosis.

It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.

Ocular delivery of angiostatic agents.

Ocular delivery of angiostatic agents.

Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes

Purpose To evaluate safety and efficacy of the angiostatic agent anecortave acetate, compared with a placebo, for treatment of subfoveal choroidal neovascularization (CNV). Design Ongoing masked, randomized, placebo-controlled, parallel evaluation of anecortave acetate (30 mg, 15 mg, and 3 mg) versus a placebo. Participants There were 128 eyes of 128 patients with subfoveal CNV secondary to age-related macular degeneration who were enrolled and treated, with 80% (102/128) of eyes presenting with predominantly classic lesions at baseline. Methods All eyes received a posterior juxtascleral depot application of masked study medication or a placebo, with retreatment at 6-month intervals if the masked investigator believed the patient could benefit. Patients received periodic detailed ophthalmic examinations with both fluorescein and indocyanine green angiography, general physical examinations with electrocardiograms, and hematology/serum chemistry/urinalysis. All ophthalmic and systemic safety data were periodically reviewed by the Independent Safety Committee overseeing the study. Main outcome measures Best-corrected logarithm of the minimum angle of resolution (logMAR) vision and fluorescein angiographic lesion characteristics were compared over time and among treatment groups. Results At month 12, anecortave acetate (15 mg) administered at 6-month intervals was statistically superior to the placebo for 3 measures of clinical efficacy: mean change from baseline vision ( P = 0.0131), stabilization of vision (<3 logMAR line change; P = 0.0323), and prevention of severe vision loss (decrease of ≥6 logMAR lines from baseline; P = 0.0224). Subgroup analysis of predominantly classic lesions revealed that anecortave acetate (15 mg) was also superior to the placebo at 1 year for each of these 3 measures of visual outcome ( Ps = 0.0022, 0.0100, and 0.0299, respectively). Anecortave acetate (15 mg) trended toward significance over the placebo at month 12 for inhibition of total lesion growth and for inhibition of both the total CNV component and the classic CNV component in both the overall and subgroup analyses. The Independent Safety Committee identified no clinically relevant treatment-related safety issues. Conclusions Anecortave acetate (15 mg) is safe and clinically efficacious at 1 year for maintaining vision, preventing severe vision loss, and inhibiting subfoveal CNV lesion growth.

Low Dose Carboplatin Combined With Angiostatic Agents Prevents Metastasis in Human Testicular Germ Cell Tumor Xenografts

Low dose chemotherapy combined with angiogenesis inhibitors has been shown to be more effective for experimental tumor treatment than chemotherapy alone. To our knowledge whether germ cell tumors could benefit from this treatment strategy remains to be evaluated. We examined the efficacy of angiostatic thrombospondin-1 (TSP-1), endostatin and combined angiostatic/low dose carboplatin in mice xenografted with human nonseminomatous germ cell tumor. We monitored tumor progression and angiogenesis in the established model of human nonseminomatous germ cell tumor xenograft in 120 SCID mice using intravital video microscopy, immunocytochemistry and real-time polymerase chain reaction. Mice received TSP-1 (20 mg/kg daily) or endostatin (10 mg/kg daily) subcutaneously (via osmotic mini pumps) for 2 weeks starting 15 days after cancer cell grafting, carboplatin cycled twice (30 mg/kg intraperitoneally days 14 and 21 after cancer cell grafting), or a combination of carboplatin with TSP-1 or endostatin. Untreated, sham and tumor bearing mice treated with Ringer's solution served as controls. Primary tumor development was not affected in mice treated with TSP-1, endostatin or carboplatin alone. All animals had metastases at 6 months, while metastasis did not develop following the combination of carboplatin with TSP-1 or endostatin. This combined therapy suppressed tumor angiogenesis, enhanced apoptosis in tumor cells and decreased vascular endothelial growth factor-A tissue mRNA expression vs controls (p <0.05). These data indicate that angiostatic agents added to low dose carboplatin have the ability to suppress the progression of human germ cell tumor xenografts toward a metastatic phenotype. Therefore, this treatment strategy might be beneficial to prevent metastasis in germ cell tumors.

New treatments in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of legal blindness in individuals 50 years and older in the developed world. Choroidal neovascularization (CNV) in exudative AMD is responsible for the majority of severe vision loss. Until recently, laser photocoagulation was the only well-established and widely accepted treatment for CNV. However, it is beneficial only for a small subset of patients, has a high rate of CNV persistence and recurrence and results in iatrogenic, collateral damage to the overlying retina. These issues make it difficult to recommend in the case of subfoveal lesions. Consequently, numerous experimental therapeutic interventions are under investigation with the common objective of destroying the CNV but leaving the foveal neurosensory retina intact. Treatment modalities can be grouped into five major categories: photodynamic therapy; radiotherapy; transpupillary thermotherapy; anti-angiogenic and angiostatic agents; and surgical intervention. The present review aims to explain the rationale behind these new treatments, analyse the evidence for their safety and efficacy, determine their stage of development and indicate in which patients they are potentially useful.