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)

Clear cell renal carcinoma (CCRC) is a highly angiogenic tumor known to secrete vascular endothelial cell growth factor (VEGF). Endostatin is an endogenous antiangiogenic agent with antitumor activity in mice. The purpose of this study was to evaluate serum levels of endostatin in normal subjects and in patients with CCRC and to examine the relationship of these levels to circulating VEGF levels. Fifteen patients (mean age, 48 years) on a clinical protocol for stage IV CCRC at the National Cancer Institute were included in the study. Archived prenephrectomy serum samples were analyzed for endostatin and VEGF concentrations. Endostatin and VEGF levels were compared with those of an age-matched group of volunteer blood donors (n = 18) using a competitive enzyme immunoassay. Data were analyzed using the Mann-Whitney U test and the Spearman rank correlation. Median serum endostatin levels were 24.6 ng/ml (range, 15.1-54.0 ng/ml) in CCRC patients versus 14.1 ng/ml (range, 1.0-19.3 ng/ml) in healthy controls (P < 0.0001). Median VEGF levels were 3.4 ng/ml (range, 0.1-11.2 ng/ml) and 2.5 ng/ml (range, 0.1-4.2 ng/ml), respectively (P = 0.065). A highly significant correlation was observed between endostatin and VEGF levels among the CCRC patients (r = 0.81, P = 0.0003) but not among controls (r = -0.22, P = 0.37). Endostatin levels are detectable in serum from healthy subjects as well as from CCRC patients. Levels are significantly elevated and correlate with VEGF levels in CCRC patients. Elucidating the nature of this correlation may lend insight into the regulation of tumor angiogenesis in patients with renal cancer.
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PMID:Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer. 1115 12

Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.
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PMID:A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis. 1115 22

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

Endostatin inhibits angiogenesis and tumor growth in mice. The role of its endogenous precursor collagen XVIII in human cancer is unknown. In normal tissues, two variants of collagen XVIII, namely, the short and long forms regulate tissue specificity, the long form being almost exclusively expressed by hepatocytes in the liver. We analyzed RNA arrays from 57 hepatocellular carcinomas (HCCs) with common and variant-specific probes and investigated the relationships between collagen XVIII expression and angiogenesis by measuring the CD34-positive microvessel density. Low collagen XVIII expression by tumor hepatocytes was associated with large tumor size (r, -0.63; P < 0.001) and replacement of trabeculae with pseudoglandular-solid architecture (chi2, 28; P < 0.001), which indicate tumor progression. Tumors expressing the highest collagen XVIII levels were smaller and had lower microvessel density (P = 0.01) than those expressing moderate levels; and HCCs with the lowest collagen XVIII levels approached a plateau of microvessel density, which indicated that a decrease in collagen XVIII expression is associated with angiogenesis in primary liver cancer. HCCs recurring within 2 years of resection showed 2.2-fold lower collagen XVIII mRNA than nonrecurring ones (P = 0.02). The findings relied on the hepatocyte-specific long form. Thus, the endogenous expression of the endostatin precursor decreases along with tumor progression in HCCs.
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PMID:Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas. 1119 95

Endostatin, a fragment of the COOH-terminal domain of mouse collagen XVIII is a recently demonstrated endogenous inhibitor of tumor angiogenesis and endothelial cell growth. Antiangiogenic therapy with endostatin in animals requires multiple and prolonged administration of the protein. Gene therapy could provide an alternative approach to continuous local delivery of this antiangiogenic factor in vivo. Established MCa-4 murine mammary carcinomas, grown in immunodeficient mice, were treated with intratumoral injection of endostatin plasmid at 7-day intervals. At the time of sacrifice, 14 days after the first injection, endostatin-treated tumor weights were 51% of controls (P < 0.01). Tumor growth inhibition was accompanied by a marked reduction in total vascular density. Specifically, computerized image analysis showed a 18-21% increase in the median distances between tumor cells and both the nearest anatomical (CD31-stained) vessel [48.1 +/- 3.8 versus 38.3 +/- 1.6 microm (P < 0.05)] and the nearest tumor-specific (CD105-stained) vessel [48.5 +/- 1.5 versus 39.8 +/- 1.5 microm (P < 0.01)]. An increased apoptotic index of tumor cells in endostatin-treated tumors [3.2 +/- 0.5% versus 1.9 +/- 0.3% (P < 0.05)] was observed in conjunction with a significant decrease in tumor perfused vessels (DiOC7 staining), and an increase in tumor cell hypoxia (EF5 staining). Hypoxia resulting from endostatin therapy most likely caused a compensatory increase of in situ vascular endothelial growth factor (VEGF) and VEGF receptor mRNA expression. Increased immunoreactivity of endostatin staining in endostatin-treated tumors was also associated with an increased thrombospondin-1 staining [1.12 +/- 0.16 versus 2.44 +/- 0.35]. Our data suggest that intratumoral delivery of the endostatin gene efficiently suppresses murine mammary carcinoma growth and support the potential utility of the endostatin gene for cancer therapy.
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PMID:Intratumoral administration of endostatin plasmid inhibits vascular growth and perfusion in MCa-4 murine mammary carcinomas. 1121 45

Based on the observation that the growth of solid tumors is dependent on the formation of new blood vessels, therapeutic strategies aimed at inhibiting angiogenesis have been proposed. A number of proteins with angiostatic activity have been described, but their development as therapeutic agents has been hampered by difficulties in their production and their poor pharmacokinetics. These limitations may be resolved using a gene therapy approach whereby the genes are delivered and expressed in vivo. Here we compared adenoviral delivery of endostatin, proliferin-related protein (PRP), and interferon-inducible protein 10 (IP10) genes. Recombinant adenoviruses carrying the three angiostatic genes express biologically active gene products as determined in vitro in endothelial cell proliferation and migration assays, and in vivo by inhibition of neoangiogenesis in rat chambers. Eradication of established tumors in vivo, in the murine B16F10 melanoma model in immunocompetent mice, was not achieved by intratumoral injection of the different vectors. However, the combination of intravenous plus intratumoral injections allowed rejection of tumors. Ad-PRP or Ad-IP10 were significantly more efficient than Ad-endostatin, leading to complete tumor rejection and prolonged survival in a high proportion of treated animals. These data support the use of in vivo gene delivery approaches to produce high-circulating and local levels of antiangiogenic agents for the therapy of local and metastatic human tumors.
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PMID:Adenovirus-mediated delivery of antiangiogenic genes as an antitumor approach. 1121 93

Angiostatin and endostatin are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vivo and tumor growth in mice. However, tumor shrinkage requires chronic delivery of large doses of these proteins. Here we report synergistic antitumor activity and survival of animals when these factors are delivered in combination to tumors by retroviral gene transfer. We have demonstrated this efficacy in both murine leukemia and melanoma models. Complete loss of tumorigenicity was seen in 40% of the animals receiving tumors transduced by the combination of angiostatin and endostatin in the leukemia model. The synergy was also demonstrated in vitro on human umbilical vein endothelial cell differentiation and this antiangiogenic activity may suggest a mechanism for the antitumor activity in vivo. These findings imply separate pathways by which angiostatin and endostatin mediate their antiangiogenic effects. Together, these data suggest that a combination of antiangiogenic factors delivered by retroviral gene transfer may produce synergistic antitumor effects in both leukemia and solid tumors, thus avoiding long-term administration of recombinant proteins. The data also suggest that novel combinations of antiangiogenic factors delivered into tumors require further investigation as therapeutic modalities.
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PMID:Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. 1123 75

Purified recombinant mouse endostatin protein has been reported to regress established murine solid tumors by inhibiting the proliferation of endothelial cells. To develop a clinical gene therapy strategy with endostatin, we cloned the cDNA of human endostatin by RT-PCR from human placenta. A 150-bp sequence encoding the IgG leader peptide was fused in frame to the 5' end of the endostatin cDNA and recombinant adenoviruses, AdENDO-YFP and AdENDO, carrying endostatin gene expression cassettes were rescued. AdENDO-YFP infects cultured mammalian cells at high efficiency and expresses a biologically active human endostatin in secreted form at high levels both in vitro and in vivo. When delivered in vivo, a strain-specific expression pattern was observed, with the highest and longest endostatin expression in 129/J mice. After systemic delivery of 2 x 10(9) PFU of AdENDO-YFP into 129/J mice, human endostatin expression was achieved at a mean value of 1.34 +/- 0.42 microg/ml of serum (n = 6) and inhibition of lung metastasis was observed in an EOMA tumor model. However, high dose intravenous delivery of AdENDO-YFP and AdENDO was associated with severe acute toxicity in recipient mice that included loss of weight, bleeding, and death of animals. These events were not observed with the injection of identical doses of a control adenovirus that did not contain the endostatin gene. Because the endostatin adenovirus-associated acute toxicity was also observed in immunodeficient NCRNU-M nude mice, the toxicity does not appear to be the result of the immunogenicity against human endostatin or the EYFP protein.
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PMID:Adenovirus-mediated human endostatin gene delivery demonstrates strain-specific antitumor activity and acute dose-dependent toxicity in mice. 1124 27

Hemangioma, the most common tumor of infancy, is a benign vascular neoplasm of unknown etiology. We show, for the first time to our knowledge, that endothelial cells from proliferating hemangioma are clonal, and we demonstrate that these hemangioma-derived cells differ from normal endothelial cells in their rates of proliferation and migration in vitro. Furthermore, migration of hemangioma endothelial cells is stimulated by the angiogenesis inhibitor endostatin, unlike the inhibition seen with normal endothelial cells. We conclude that hemangiomas constitute clonal expansions of endothelial cells. This is consistent with the possibility that these tumors are caused by somatic mutations in one or more genes regulating endothelial cell proliferation.
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PMID:Clonality and altered behavior of endothelial cells from hemangiomas. 1125 64

Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in approximately 80% inhibition of preexisting tumor growth in murine models involving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (BxPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angiostatin, endostatin, or neuropilin were significantly less effective. A strong correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative analyses of different therapeutic approaches that target tumor angiogenesis and provide a rationale for the selection of specific antiangiogenic gene products as lead candidates for use in gene therapy approaches aimed at the treatment of malignant and ocular disorders.
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PMID:Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. 1127 74


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