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)

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. Vascular endothelial growth factor (VEGF) and its receptors, VEGF-receptor 1 (VEGF-R1; FLT-1) and VEGF-R2 (KDR), have been shown to play a major role in tumor angiogenesis. PTK787/ZK 222584, a specific inhibitor of both VEGF-receptor tyrosine kinases, was investigated for its antitumoral and antiangiogenic activity in a murine renal cell carcinoma model. After intrarenal application of the renal carcinoma cells, mice develop a primary tumor and metastases to the lung and to the abdominal lymph nodes. Daily oral therapy with PTK787/ZK 222584 at a dose of 50 mg/kg resulted in a significant decrease of 61 and 67% in primary tumors after 14 and 21 days, respectively. The occurrence of lung metastases was significantly inhibited at both time points (98% reduction and 78% reduction, respectively). After 14 days, no lymph node metastases developed in the PTK787/ZK 222584-treated group, whereas after 21 days of treatment, the lymph node metastases were reduced by 87%. Vessel density in tumor tissues, detected by immunohistochemistry with an anti-CD31 antibody, was significantly decreased by PTK787/ZK 222584. Using color Doppler imaging ultrasound, significant changes in blood flow in the tumor feeding renal artery were found under treatment with PTK787/ZK 222584. Blood flow changes correlated with changes in vessel density but not with tumor volume. The compound was well tolerated in all in vivo experiments and had no significant effects on body weight or general well-being of the animals. This was in contrast to the animals treated with the antiangiogenic agent TNP-470. s.c. therapy with 30 mg/kg TNP-470 every other day had to be discontinued after 13 days because of animal weight loss (>20%) and ataxia. These results demonstrate that PTK787/ZK 222584 is a potent inhibitor of tumor growth, metastases formation, and tumor vascularization in murine renal cell carcinoma. Furthermore, we have been able to demonstrate that color Doppler imaging ultrasound can be used to measure blood flow to a tumor and that flow correlates with vessel density. Thus, this may be a valuable noninvasive method for monitoring the effects of antiangiogenic agents such as PTK787/ZK 222584 on tumor vasculature.
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PMID:Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. 1098 92

Most solid-tumor malignancies remain incurable. Novel agents that target and counteract biologic mechanisms are now being developed. It is hoped that these drugs will allow for more effective, less toxic cancer treatments and long-term maintenance approaches. One important class of agents functions by an anti-angiogenic mechanism, targeting the blood vessel supply of the tumor and inhibiting tumor growth. Several principles are common to these new agents. First, because many of these agents are growth-inhibiting molecules that work exclusively against the tumor vasculature, single agents will have little effect on tumor size in advanced disease. Second, because these agents are relatively non-toxic, they are unlikely to induce the side effects associated with chemotherapy. Because endothelial cells seldom divide in a human host, anti-angiogenic compounds are expected to produce little toxicity. Third, most of these agents work synergistically with chemotherapy and/or radiotherapy. Ironically, combining these relatively non-toxic agents with chemotherapy often produces the toxicities usually associated with anticancer regimens. Anti-angiogenic agents might ultimately be studied in minimal disease. Clinical studies must demonstrate that these agents affect tumor vasculature, and phase I trials should include built-in surrogate endpoints. This article defines the general principles of anti-angiogenic drug action and explains how these principles have been used to design a phase I trial of human endostatin.
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PMID:Clinical studies of angiogenesis inhibitors: the University of Texas MD Anderson Center Trial of Human Endostatin. 1117 45

A number of endogenous inhibitors targeting the tumor vasculature have recently been identified using in vitro and in vivo antiangiogenesis models. While many of these angiogenesis inhibitors display a broad spectrum of biological actions on several systems in the body, several inhibitors including angiostatin, endostatin, and serpin antithrombin seem to act specifically on the proliferating endothelial cell compartment of the newly formed blood vessels. The discovery of these specific endothelial inhibitors not only increases our understanding of the functions of these molecules in the regulation of physiological and pathological angiogenesis, but may also provide an important therapeutic strategy for the treatment of cancer and other angiogenesis dependent diseases, including diabetic retinopathy and chronic inflammations. Systemic administration of these angiogenesis inhibitors in animals significantly suppresses the growth of a variety of tumors and their metastases. However, their production as functional recombinant proteins has been proven to be difficult. In addition, high dosages of these inhibitors are required to suppress tumor growth in animal studies. Other disadvantages of the antiangiogenic protein therapy include repeated injections, prolonged treatment, transmission of toxins and infectious particles, and high cost for manufacturing large amounts of protein molecules. Thus, alternative strategies need to be developed in order to improve the clinical settings of antiangiogenic therapy. Developments of these strategies are ongoing and they include identification of more potent inhibitors, antiangiogenic gene therapy, improvement of protein/compound half-lives in the circulation, increase of their concentrations at the disease location, and combinatorial therapies with approaches including chemotherapy, radiotherapy, and immunotherapy. Despite the above-mentioned disadvantages, a few inhibitors have entered into the early stages of clinical trials and they may bring new hopes for the treatment of cancer and other angiogenesis dependent diseases.
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PMID:Endogenous angiogenesis inhibitors and their therapeutic implications. 1131 6

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable new approach to cancer therapy. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg, anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis, such as endostatin and angiostatin. Therapy with endogenous angiogenic inhibitors such as endostatin and angiostatin may reverse the angiogenic switch preventing growth of tumor vasculature. Preclinical studies have shown that endostatin effectively inhibits tumor growth and shrinks existing tumor blood vessels. Phase 1 clinical trials of endostatin and angiostatin are ongoing, and preliminary results show minimal toxicities.
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PMID:Role of angiogenesis in tumor growth and metastasis. 1251 34

Tumor growth, local invasion, and metastatic dissemination are dependent on the formation of new microvessels. The process of angiogenesis is regulated by a balance between pro-angiogenic and anti-angiogenic factors, and the shift to an angiogenic phenotype (the "angiogenic switch") is a key event in tumor progression. The use of anti-angiogenic agents to restore this balance represents a promising approach to cancer treatment. Known physiological inhibitors include trombospondin, several interleukins, and the proteolytic break-down products of several proteins. Angiostatin, an internal fragment of plasminogen, is one of the more potent of this latter class of angiogenesis inhibitors. Like endostatin, another anti-angiogenic peptide derived from collagen XVIII, angiostatin can induce tumor vasculature regression, leading to a complete cessation of tumor growth. Inhibitors of angiogenesis target normal endothelial cells, therefore the development of resistance to these drugs is unlikely. The efficacy of angiostatin has been demonstrated in animal models for many different types of solid tumors. Anti-angiogenic cancer therapy with angiostatin requires prolonged administration of the peptide. The production of the functional polypeptides is expensive and technical problems related to physical properties and purity are frequently encountered. Gene transfer represents an alternative method to deliver angiostatin. Gene therapy has the potential to produce the therapeutic agent in high concentrations in a local area for a sustained period, thereby avoiding the problems encountered with long-term administration of recombinant proteins, monoclonal antibodies, or anti-angiogenic drugs. In this review we compare the different gene therapy strategies that have been applied to angiostatin, with special regard to their ability to provide sufficient angiostatin at the target site.
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PMID:Inhibition of tumor angiogenesis by angiostatin: from recombinant protein to gene therapy. 1290 56

Despite aggressive surgery and post-operative radiation and chemotherapy, the prognosis is poor for glioblastoma patients. Anti-angiogenic therapy with compounds such as endostatin could delay the onset of relapse. However, the short systemic half-life of this proteins as well as the blood-brain barrier makes the use of this therapy difficult for brain cancer patients. The aim of this project is to develop and implant genetically engineered producer cells secreting endostatin that are encapsulated in calcium cross-linked alginate gel beads. Encapsulation of cells within alginate gels has a potential as a sustained release system in addition to the fact that the encapsulation technology protects the cells from rejection by the immune system. Human embryonal kidney 293 cells have been transfected with the gene for endostatin. These cells have been encapsulated in calcium cross-linked alginate gels and optimized for the secretion of endostatin. Alginate gel beads implanted into rat brain have shown only a moderate loss in cell viability but extended endostatin release for periods of up to 12 months. Visualization of the anti-angiogenic effect on C6 rat glioma growth, tumor vasculature and microhemodynamics has been demonstrated by using intravital video microscopy. The data indicates that endostatin greatly affects tumor-associated microcirculation but does not appear to affect normal microcirculation. The local delivery of endostatin seems to specifically affect tumor-associated microvessels by reduction of the vessel density, diameter and functionality. Tumor cell migration and invasion was greatly reduced in the endostatin treated animals.
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PMID:Cell therapy using encapsulated cells producing endostatin. 1453 71

Endostatin is a potent inhibitor of angiogenesis currently in phase I clinical trials. Imaging technologies that use near-infrared fluorescent probes are well suited to the laboratory setting. The goal of this study was to determine whether endostatin labeled with a near-infrared probe (Cy5.5) could be detected in an animal and whether it would selectively localize to a tumor. Endostatin was conjugated to Cy5.5 monofunctional dye and injected into mice bearing Lewis lung carcinoma tumors (350 mm2). Mice were imaged at various time points while under sedation using a lightproof box affixed to a fluorescent microscope mounted with a filter in the near-infrared bandwidth consistent with Cy5.5 fluorescence. After i.p. injection, endostatin-Cy5.5 was absorbed producing a near-infrared fluorescent image within the tumors at 18 h reaching a maximum at 42 h after injection. No signal was emitted from mice injected with unlabeled endostatin or Cy5.5 dye alone or those that received no injection. Further results show that a dose response exists with injection of endostatin-Cy5.5. Mimicking the clinical route of administration, an i.v. injection had a peak signal emission at 3 h but also persisted to 72 h. Finally, to determine the intratumoral binding site for endostatin, we performed immunofluorescence on tumor specimens and demonstrated that endostatin binds to tumor vasculature and colocalizes with platelet/endothelial cell adhesion molecule 1 expression. This study demonstrates that endostatin covalently bound to Cy5.5 will migrate from a distant i.p. injection site to a tumor. These data indicate that endostatin-Cy5.5 is appropriate for selectively imaging tumors in uninjured experimental animals.
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PMID:In vivo tumor imaging in mice with near-infrared labeled endostatin. 1507 92

We have demonstrated that the designed peptide anginex displays potent antiangiogenic activity. The aim of our study was to investigate the effect of anginex on established tumor vasculature as an adjuvant to radiation therapy of solid tumors. In the MA148 human ovarian carcinoma athymic mouse model, anginex (10 mg/kg) in combination with a suboptimal dose of radiation (5 Gy once weekly for 4 weeks) caused tumors to regress to an impalpable state. In the more aggressive SCK murine mammary carcinoma model, combination of anginex and a single radiation dose of 25 Gy synergistically increased the delay in tumor growth compared to the tumor growth delay caused by either treatment alone. Immunohistochemical analysis also demonstrated significantly enhanced effects of combined treatment on tumor microvessel density and tumor or endothelial cell proliferation and viability. In assessing physiologic effects of anginex, we observed a reduction in tumor perfusion and tumor oxygenation in SCK tumors after 5-7 daily treatments with anginex with no reduction in blood pressure. To test anginex as a radiosensitizer, additional studies using SCK tumors were performed. Three daily i.p. injections of anginex were able to enhance the effect of 2 radiation doses of 10 Gy, resulting in 50% complete responses, whereas the known antiangiogenic agent angiostatin did not enhance the radiation response of SCK tumors. Mechanistically, it appears that anginex functions as an endothelial cell-specific radiosensitizer because anginex showed no effect on in vitro radiosensitivity of SCK or MA148 tumor cells, whereas anginex significantly enhanced the in vitro radiosensitivity of 2 endothelial cell types. This work supports the idea that the combination of the antiangiogenic agent anginex and radiation may lead to improved clinical outcome in treating cancer patients.
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PMID:Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells. 1568 84

Therapeutic targeting of the tumor vasculature that destroys preexisting blood vessels of the tumor and antiangiogenesis therapy capitalize on the requirement of tumor cells on an intact vascular supply for oxygen and nutrients for growth, expansion and metastasis to the distal organs. Whereas these classes of agents show promise in delaying tumor progression, they also create glucose and oxygen deprivation conditions within the tumor that could trigger unintended prosurvival responses. The glucose-regulated protein GRP78, a major endoplasmic reticulum chaperone, is inducible by severe glucose depletion, anoxia, and acidosis. Here we report that in a xenograft model of human breast cancer, treatment with the vascular targeting agent, combretastatin A4P, or the antiangiogenic agent, contortrostatin, promotes transcriptional activation of the Grp78 promoter and elevation of GRP78 protein in surviving tumor cells. We further show that GRP78 is overexpressed in a panel of human breast cancer cells that has developed resistance to a variety of drug treatment regimens. Suppression of GRP78 through the use of lentiviral vector expressing small interfering RNA sensitizes human breast cancer cells to etoposide-mediated cell death. Our studies imply that antivascular and antiangiogenesis therapy that results in severe glucose and oxygen deprivation will induce GRP78 expression that could lead to drug resistance.
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PMID:Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. 1599 54

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


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