Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of angiogenesis offers an alternative approach to cancer chemotherapy, since solid tumor growth has an absolute dependency on angiogenesis. We have previously shown that 8,9-dihydroxy-7-methyl-benzo [b]quinolizinium bromide (GPA1734) is a basement membrane synthesis inhibitor, and that this compound acts as an antiangiogenic agent in the chick chorioallantoic membrane. When a piece of 10 mg from a Walker 256 carcinoma was implanted into the peritoneal cavity of rats, tumor grew to about 15 g within nine days after transplant. Daily treatment of Walker 256 carcinoma bearing animals with GPA1734, at doses 10-100 mg/kg intraperitoneally, restrained tumor growth in a dose dependent manner. Macroscopic examination showed tumor cells growing in spherical masses 5-8 mm in diameter, indicative of absence of neovascularization. GPA1734 at 300 microM had no direct effect on Walker 256 carcinoma cell culture growth. The antitumor effect of this agent on Walker 256 carcinoma may be related to its antiangiogenic properties.
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PMID:Antitumor effect of GPA1734 in rat Walker 256 carcinoma. 238 1

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.
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PMID:Angiogenesis: regulators and clinical applications. 1117 29

Neovascularization is increasingly recognized as an important factor in the pathogenesis of hematologic malignancies as well as solid tumors. The complex interactions between several cell types and numerous cytokine mediators suggest the involvement of autocrine and paracrine signaling mechanisms. Vascular endothelial growth factor (VEGF) in particular is critical to both stimulation of leukemic growth and proliferation of endothelial cells. Tyrosine kinase receptors specific for certain growth factors represent attractive target molecules for anticancer therapy. SU5416 is a competitive inhibitor of VEGF receptor subtypes VEGFR-1 and VEGFR-2 and stem cell factor receptor c-kit. Preclinical evidence shows that SU5416 effectively inhibits VEGF-induced endothelial cell proliferation and slows growth of subcutaneous solid tumor xenografts. This agent is in late-stage clinical trials in patients with solid tumors, and a Phase 2 study was recently initiated to evaluate its utility in the treatment of acute myeloid leukemia. In this Phase 2 study, investigators are seeking to determine the response rate to the antiangiogenic agent SU5416. Translational research in this study is intended to aid our understanding of the precise mechanisms by which SU5416 affects acute myeloid leukemia cells and the bone marrow microenvironment.
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PMID:Role of angiogenesis inhibitors in acute myeloid leukemia. 1177 83

Since angiogenesis is essential for the growth of any solid tumor, emerging efforts are being made to develop antiangiogenic therapy. To date, however, no antiangiogenic agent has become widely available for the clinical setting. Angiotensin I-converting enzyme (ACE) inhibitors are commonly used as antihypertensive agents and it has recently been suggested that they decrease the risk of cancer. Studies have found that an ACE inhibitor, perindopril, is a potent inhibitor of experimental tumor development and angiogenesis at a clinically comparable dose. The potent angiogenic factor, vascular endothelial growth factor (VEGF), is significantly suppressed by perindopril and also inhibits VEGF-induced tumor growth. In vitro studies showed that perindopril is not cytotoxic to either tumor cells or endothelial cells. Since perindopril is already in widespread clinical use without serious side effects, it may represent a potential new strategy for anticancer therapy.
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PMID:Perindopril: possible use in cancer therapy. 1198 65

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.
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PMID:Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor. 1499 40

Previous experiments have shown that a vascular endothelial growth factor (VEGF)-DT385 toxin conjugate inhibits endothelial cell proliferation, angiogenesis and solid tumor growth in a xenotransplant model system. Here, we report that VEGF-DT385 toxin conjugate effectively inhibits spontaneous tumorigenesis. The C3(1)/SV40 TAg transgenic mouse model of mammary gland carcinogenesis was used to determine the effectiveness of VEGF-DT385 toxin conjugate in delaying the onset of disease and the development of solid tumors. Animals were treated daily with conjugate for a period of 7 days. Therapy was initiated at week 14 of development before any visible adenocarcinomas were evident. Treatment of mice with VEGF-DT385 toxin conjugate significantly delayed the onset of tumorigenesis and inhibited solid tumor growth by more than 92%. Furthermore, conjugate treated animals showed less than twice the number of tumor nodules when compared to control mice. Finally, this vascular targeting agent significantly increased survival time of animals by 5 weeks. VEGF-DT385 toxin conjugate resulted in temporary weight loss and no long-lasting toxicity was seen. More importantly, using this established tumor model, VEGF-DT385 toxin conjugate appeared to be as effective as a similar treatment schedule with recombinant human endostatin. Our results suggest that VEGF-DT385 toxin conjugate is a potent inhibitor of mammary adenocarcinoma growth and might be useful in breast cancer therapy.
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PMID:VEGF-DT385 toxin conjugate inhibits mammary adenocarcinoma development in a transgenic mouse model of spontaneous tumorigenesis. 1511 74

Angiogenesis is essential for solid tumor growth. Although successful antiangiogenic therapies have been demonstrated in animal models, a systematic comparison of the efficacy of different antiangiogenic factors has not been described in the hepatic environment. To address this issue, CT26 murine colon carcinoma cells were transfected with retroviral vectors encoding murine endostatin (mEndostatin), human angiostatin (hAngiostatin), murine-soluble vascular endothelial growth factor receptor-2, (msFlk-1), or murine-soluble Tie2 (msTie2). The transfected cells were then subjected to another round of transfection with a luciferase cDNA-encoding retroviral vector. Expression of these putative antiangiogenic proteins inhibited the proliferation of human umbilical vein endothelial cells in vitro but not tumor cells. To examine effects on tumor growth in vivo, modified cells were delivered via intrasplenic injection into BALB/c mice to induce liver metastases. Tumor burden was measured weekly by bioluminescence. Growth of hepatic metastases in vivo was significantly reduced in mice that were administered cells expressing msTie2 (76% reduction compared with control cells 21 days after intrasplenic inoculation; P < 0.05). Similar results were observed with cells that expressed msFlk-1 and hAngiostatin. However, expression of mEndostatin had no significant effect on the growth of liver metastases compared with control animals. These findings indicate that multiple antiangiogenic pathways are necessary for the growth of hepatic metastases, and each of these pathways is a potential clinically relevant antiangiogenic target for the treatment of this disease.
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PMID:A comparison of antiangiogenic therapies for the prevention of liver metastases. 1624 20

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.
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PMID:Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion. 1627 8

Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis and a promising anticancer agent capable of suppressing solid tumor growth in animal cancer models. We have previously shown that PEDF can be phosphorylated and that distinct phosphorylation states of this factor differentially regulate its physiologic function. Here, we report that phosphomimetic mutants of PEDF, which possess significantly increased antiangiogenic activity, are much more efficient than wild-type (WT) PEDF in inhibiting growth and neovascularization in MDA-MB-231 (breast cancer), HCT116 (colon cancer), and U87-MG (glioblastoma) xenograft models. Importantly, the antitumor activity of the phosphomimetic mutants is comparable with that of the established antiangiogenic agent bevacizumab. However, unlike bevacizumab, these compounds act in a vascular endothelial growth factor (VEGF)-independent manner, as they do not affect the levels of VEGF-A mRNA and VEGF receptor 2 phosphorylation. Further immunohistochemical analysis revealed that PEDF mutants affect mainly tumor-residing endothelial cells and prevent the formation of intratumoral vascular network by facilitating endothelial cell apoptosis. It was also found that PEDF mutants reduce survival of endothelial cells in culture much better than WT-PEDF, an effect that is apparent even in the presence of VEGF or basic fibroblast growth factor, and promote much stronger endothelial cell apoptosis. On the other hand, PEDF and its mutants did not affect survival of cultured cancer cells, indicating that the antiangiogenic activity of these agents is the foremost element of the observed antitumor effect. These findings have specific implications on improving the properties of WT-PEDF, which is currently in preclinical development, and encourage the development of PEDF mutants as specific, neovascularization-targeting anticancer agents.
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PMID:Phosphomimetic mutants of pigment epithelium-derived factor with enhanced antiangiogenic activity as potent anticancer agents. 2061 Jun 33

Angiogenesis is one of the key acquired characteristics or "hallmarks" essential for the growth and development of all solid tumor types. The antiangiogenic agent vascular endothelial growth factor-Trap (VEGF-Trap) (aflibercept), which is a composite decoy receptor based on VEGF receptor-1 and VEGF receptor-2 fused to an Fc segment of immunoglobulin G1 that binds specifically to VEGF, has demonstrated preclinical efficacy in a range of different tumor types. VEGF-Trap exerts its antiangiogenic effects through regression of tumor vasculature, remolding or normalization of surviving vasculature, and inhibition of new tumor vessel growth. Preclinical and clinical studies have reported that VEGF-Trap can be combined effectively with both chemotherapy and radiotherapy. This review examines the main effects of VEGF-Trap on tumor vasculature and on different types of solid tumors, and explores the preclinical and clinical benefits of incorporating VEGF-Trap into anticancer treatment strategies.
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PMID:Clinical applications of VEGF-trap (aflibercept) in cancer treatment. 2087 16


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