Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liposomes have been used therapeutically to deliver drugs to certain anatomical sites. The use of liposomes to deliver antigens, although not a new concept, has received less attention. At least two vaccines of nearly identical liposome base composition to our vaccines have been tested in humans. A malaria vaccine study showed that the liposomal preparation is quite safe: reaction profiles of volunteers receiving the vaccine demonstrated little reactivity and virtually no pyrogenicity (14). The concentration of MPLA in the vaccine was substantially higher (nearly 50,000 times) than the pyrogenic dose of free lipid A. The same vaccine, but different antigen (gp120, an HIV protein), was tested in volunteers and had the same lack of toxicity (27). In both studies, antibodies and cytotoxic cells specific for the respective antigens were produced. We have several subunit vaccines under development for infectious diseases (gram negative sepsis, fungal infections, protozoan infections), metabolic disorders (hypercholesterolemia, diabetic retinopathy, macular degeneration), and neoplastic diseases (multi-drug resistant cancer, primary and metastatic tumors, and angiogenic hyperproliferative disorders). In each case, one or more antigens were identified that might be useful in immunologic control of biologic proliferation (i.e., pathogen or tumor growth, rise in serum cholesterol, growth of blood vessels). We anticipate that at least one of these vaccines will be ready for testing in humans in the next calendar year.
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PMID:Liposomal vaccines. 864 17

Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis associated with tumors and other pathological conditions, including proliferative diabetic retinopathy and age-related macular degeneration. The murine anti-human VEGF monoclonal antibody (muMAb VEGF) A.4.6.1 has been shown to potently suppress angiogenesis and growth in a variety of human tumor cells lines transplanted in nude mice and also to inhibit neovascularization in a primate model of ischemic retinal disease. In this report, we describe the humanization of muMAb VEGF A.4.6.1. by site-directed mutagenesis of a human framework. Not only the residues involved in the six complementarity-determining regions but also several framework residues were changed from human to murine. Humanized anti-VEGF F(ab) and IgG1 variants bind VEGF with affinity very similar to that of the original murine antibody. Furthermore, recombinant humanized MAb VEGF inhibits VEGF-induced proliferation of endothelial cells in vitro and tumor growth in vivo with potency and efficacy very similar to those of muMAb VEGF A.4.6.1. Therefore, recombinant humanized MAb VEGF is suitable to test the hypothesis that inhibition of VEGF-induced angiogenesis is a valid strategy for the treatment of solid tumors and other disorders in humans.
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PMID:Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. 2758 49

Angiogenesis, the sprouting of new blood vessels, plays a role in diverse disease states including cancer, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, psoriasis, atherosclerosis, and restenosis. With regard to cancer, the clinical association of tumor vascularity with tumor aggressiveness has been clearly demonstrated in numerous tumor types. The observation of increased microvessel density in tumors not only serves as an independent prognostic indicator, but also suggests that anti-angiogenic therapy may be an important component of treatment regimens for cancer patients. The complexity of the angiogenic process, which involves both positive and negative regulators, provides a number of targets for therapy. Many positive regulators, including growth factor receptors, matrix metalloproteinases, and integrins, have been correlated with increased vascularity of tumors and poor prognosis for patient survival. Thus, these serve as ideal targets for anti-angiogenesis therapy. Many inhibitors of these targets are currently undergoing clinical evaluation as potential anti-cancer agents. In this article, we discuss the role of positive regulators in angiogenesis and tumor growth and describe the anti-angiogenic agents under development.
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PMID:New paradigms for the treatment of cancer: the role of anti-angiogenesis agents. 1081 76

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.
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PMID:Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. 1251 33

Ischemic retinal diseases, such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration, are a major cause of blindness worldwide. Angiostatin is an internal peptide fragment of plasminogen that inhibits endothelial proliferation in vitro and tumor growth in vivo. We now demonstrate that HIV vector encoding angiostatin (HIV-angiostatin) can inhibit retinal neovascularization in a mouse model of proliferative retinopathy. Intravitreal injections of HIV-angiostatin led to stable expression of the angiostatin gene in retinal tissue. Retinal neovascularization was histologically quantitated by a masked protocol. Retinal neovascularization in the eye injected with HIV-angiostatin was reduced in 90% (9/10; P=0.025) of animals, compared with the eye injected with phosphate-buffered saline. Reduction of histologically evident neovascular nuclei per 6-microm section averaged 68%, with maximal inhibitory effects of 87%. Neovascularization was not reduced in the eyes injected with HIV vector encoding enhanced green fluorescent protein. This is the first report that HIV-angiostatin can reduce neovascular cell nuclei in a murine proliferative retinopathy model. These data suggest that the anti-angiogenic activity of angiostatin has therapeutic potential for the treatment of retinal neovascularization.
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PMID:Lentivirus-mediated expression of angiostatin efficiently inhibits neovascularization in a murine proliferative retinopathy model. 1257 29

Tumor angiogenesis affords new targets for cancer therapy, since inhibition of angiogenesis suppresses tumor growth by cutting out the supply of oxygen and nutrients. Anti-angiogenic therapy is thought to be free of the severe side effects that are usually seen with cytotoxic anticancer drugs. Furthermore, anti-angiogenic therapy is thought not only to eradicate primary tumor tissues, but also to suppress tumor metastases. However, it is uncertain whether this therapy causes tumor regression because it inhibits only angiogenic events. Recently, a novel anti-angiogenic therapy called anti-neovascular therapy (ANET) has become notable. This therapy inflicts indirect lethal damage on tumor cells by damaging newly formed blood vessels using anti-cancer drugs targeting the angiogenic vasculature, since cytotoxic anti-cancer drugs cause damage to proliferating neovascular endothelial cells as well as tumor cells. Moreover, neovascular endothelial cells would not be expected to acquire drug-resistance. Traditional chemotherapy, which directly targets tumor cells, has potential problems such as low specificity and severe side effects. On the contrary, in ANET, severe side effects may be suppressed, since traditional anti-cancer agents are delivered to the neovessels by DDS technology. Besides the usage of DDS technology, anti-neovascular scheduling of chemotherapy, or metronomic-dosing chemotherapy, has also been attempted in which anti-cancer drugs are administered on a schedule to damage neovessels. In this review, we describe traditional anti-angiogenic therapy and ANET. We also discuss anti-angiogenic cancer photodynamic therapy (PDT), since PDT is clinically applied to treat age-related macular degeneration (AMD), in which uncontrolled angiogenesis occurs.
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PMID:Cancer anti-angiogenic therapy. 1513 29

Pigment epithelium-derived factor (PEDF) is the most potent endogenous inhibitor of angiogenesis in age-related macular degeneration and tumors. However, the molecular mechanism of the anti-angiogenic activity of PEDF is poorly understood. PEDF interacts with the extracellular matrix (ECM) in vitro. Here, we investigated the possible involvement of the motif for ECM interaction in the anti-angiogenic activity of PEDF. The growth rates of HeLa cells in culture were not affected by transfection of PEDF, indicating that PEDF did not suppress tumor cell growth directly. In tumor xenografts, the overexpression of wild-type PEDF significantly suppressed tumor growth, whereas a mutant of the collagen I-binding site of PEDF (Col-mut PEDF) did not inhibit tumor growth. A mutant of the heparin-binding site of PEDF (Hep-mut PEDF) suppressed tumor growth. Histological analysis showed that the density and area of microvasculatures in either PEDF or Hep-mut PEDF were suppressed when compared with those in either vector or Col-mut PEDF. Our data indicate that PEDF inhibits tumor growth via its anti-angiogenic activity, and the collagen I-binding motif of PEDF is involved in the biological activity.
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PMID:Involvement of the collagen I-binding motif in the anti-angiogenic activity of pigment epithelium-derived factor. 1610 27

The concept of anti-angiogenesis therapy was introduced by Judah Folkman in 1971 and since then, a plethora of pro- and anti-angiogenic factors have been identified. In the recent years, it has become clear that angiogenesis, the formation of new capillaries from a pre-existing capillary network, is highly regulated by the action of pro- and anti-angiogenic factors. In the healthy adult organism the "angiogenic-switch" is likely turned "Off", i. e. anti-angiogenic factors are likely counteracting the pro-angiogenic factors resulting in a non-angiogenic state. Angiogenesis is encountered during wound healing processes, the female menstrual cycle and endometrial remodeling, as well as during embryonic development and organ growth. In the pathological setting, angiogenesis plays an important role in different diseases like rheumatoid arthritis, psoriasis, macular degeneration, diabetic retinopathy, and tumor growth. In this regard, recent studies have described several endogenous inhibitors of angiogenesis, with a subset derived from extracellular matrix (ECM) proteins. This review will particularly focus on the type IV collagen-derived angiogenesis inhibitors Arresten, Canstatin and Tumstatin.
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PMID:Type IV collagen-derived angiogenesis inhibitors. 1760 10

Angiogenesis is the formation of new blood vessels from pre-existing vessels to form capillary networks, which, among other diseases, such as diabetic retinopathy and macular degeneration, is particularly important for tumor growth and metastasis. Thus, depriving a tumor of its vascular supply by means of anti-angiogenic agents has been of great interest since its proposal in the 1970s. This review looks at the common angiogenic inhibitors (angiostatin, endostatin, maspin, pigment epithelium-derived factor, bevacizumab and other monoclonal antibodies, and zoledronic acid) and their current status in clinical trials.
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PMID:Angiogenesis inhibitors and the need for anti-angiogenic therapeutics. 1789 Jun 68

In adults, angiogenic abnormalities are involved in not only tumor growth but several human inherited diseases as well. It is unclear, however, concerning how the normal vascular structure is maintained and how angiogenesis is initiated in normal adults. Using the Cre-LoxP-mediated conditional gene deletion, we show in the present study that in adult mice disruption of the transcription factor recombination signal-binding protein Jkappa (RBP-J) in endothelial cells strikingly induced spontaneous angiogenesis in multiple tissues, including retina and cornea, as well as in internal organs, such as liver and lung. In a choroidal neovascularization model, which mimics the angiogenic process in tumor growth and age-related macular degeneration, RBP-J deficiency induced a more intensive angiogenic response to injury. This could be transmitted by bone marrow, indicating that RBP-J could modulate bone marrow-derived endothelial progenitor cells in adult angiogenesis. In addition, in the absence of RBP-J, proliferation of endothelial cells increased significantly, leading to accumulative vessel outgrowth. These findings suggest that in adults RBP-J-mediated Notch signaling may play an essential role in the maintenance of vascular homeostasis by repressing endothelial cell proliferation.
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PMID:RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. 1809 13


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