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

A novel naturally occurring antiangiogenic agent isolated from cartilage, referred to as Neovastat (AE-941), was examined for its efficacy against tumor neovascularization and progression. Exposure to Neovastat results in ex ovo antiangiogenic properties in the chorioallantoid membrane of chicken embryo (71% decrease in the angiogenic index as compared to the basic fibroblast growth factor (bFGF) treated control embryos, P < 0.0001). Oral administration of Neovastat inhibits bFGF-induced angiogenesis in the Matrigel mouse model (87.5% decrease in hemoglobin as compared to the bFGF-treated control implants, P < 0.0001). Neovastat also induces a dose response decrease of lung metastases in the Lewis lung carcinoma model (oral administration; 69.1% of inhibition obtained at the maximal dose of 0.5 ml/day, P < 0.0001). Combined with a sub-optimal dose of cisplatinum (2 mg/kg, i.p.), Neovastat (0.5 ml/day) improved the therapeutic index by increasing the antimetastatic efficacy and by exerting a protective activity against cisplatinum-induced body weight loss and myelosuppression. In summary, our experimental data provide evidence of antiangiogenic and antimetastatic properties of Neovastat, following oral administration.
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PMID:Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. 1196 78

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.
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PMID:Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction. 1207 78

Angiogenesis, an essential phenotype for tumor formation, requires the interaction of many cells within the tumor microenvironment. Therefore, successful antiangiogenic therapies must be able to block all of the different mechanisms tumors use to induce neovascularization. A major challenge for developing such protocols is determining which agents are likely to have the highest degree of synergistic activity in vivo. We treated human microvascular endothelial cells with six inhibitors of angiogenesis and used microarrays to seek divergent patterns of gene expression suggestive of potential synergies. The expression profiles of a thrombospondin-mimetic peptide (DI-TSPa) and TNP-470 (TNP) were very similar, whereas endostatin had a dramatically different profile. In vitro, endostatin was synergistically antiangiogenic with either TNP-470 or DI-TSPa. In vivo, mice bearing Lewis lung carcinoma cells treated with a combination of endostatin and either DI-TSPa or TNP-470, at doses that were ineffective when used alone, resulted in a marked inhibition of tumor growth and decreased tumor angiogenesis. Conversely, animals treated with both DI-TSPa and TNP-470 demonstrated a modest effect on both tumor growth and angiogenesis. These results suggest that even in the absence of a complete mechanistic understanding of how these inhibitors work, gene expression profiling may be used to predict synergistic antiangiogenic activity and thus maximize their antitumor efficacy.
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PMID:Prediction of in vivo synergistic activity of antiangiogenic compounds by gene expression profiling. 1249 46

Endostatin has been considered a highly specific inhibitor of endothelial cell proliferation and/or migration. To explore the use of endostatin in antiangiogenic gene therapy, we generated a recombinant adenovirus, AdEndo, carrying the gene for mouse endostatin. Injection of 10(9) PFU of AdEndo resulted in a low but significant suppression (25%) of preestablished tumor growth in murine models involving murine Lewis lung carcinoma (LLC) and human breast cancer MDA-MB-231 tumors. Greater anticancer activity was observed when the same dose of AdEndo was injected into two other preestablished murine models involving C51 murine colon cancer and HT29 human colon cancer (55 and 47% tumor growth reduction, respectively). In vitro, endostatin derived from AdEndo-infected MRC-5 fibroblasts inhibited the growth of C51 and HT29 cell lines (72 and 61%, respectively). The extent of this inhibition was comparable to that observed in endothelial cells: 75% for microcapillary endothelial cell line HMEC-1, 52% for human dermal microvascular endothelial cells, 46% for human umbilical vein endothelial cells, and 67% for calf pulmonary arterial endothelial cells. Both endothelial and colon cancer cells showed a clear increase in cell apoptosis (4- to 5-fold for endothelial cells and 5- to 10-fold for colon cancer cells) and an accumulation in the G(1) phase of the cell cycle. This antiproliferative activity was not observed in other tumor cell lines: LLC, MDA-MB-231, murine colon adenocarcinoma MC38, human prostate cancer cell line DU145, and human breast cancer cell line CAL51. Taken together, these results provide evidence that, in addition to its antiangiogenic activity, endostatin exerts a direct anticancer action that appears to be restricted to some tumor cell lines. Thus, endostatin could be used in some colon cancer treatments and its clinical efficacy would depend on the response of tumor cells themselves.
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PMID:Endostatin exhibits a direct antitumor effect in addition to its antiangiogenic activity in colon cancer cells. 1286 17

It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
Lung Cancer 2003 Dec
PMID:Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer. 1461 19

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC.
Clin Lung Cancer 2002 Mar
PMID:Targeted therapy using novel agents in the treatment of non-small-cell lung cancer. 1472 Mar 53

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

Targeting cells that support tumor growth by administering potent angiogenesis inhibitors is currently an area of intense interest. In the present study, a unique plasmid vector for the mouse endostatin gene, pXLG-mEndo, was constructed and evaluated with and without radiation using the Lewis lung carcinoma (LLC) cell line. The physical properties of the expressed endostatin protein were validated by PCR, gel electrophoresis, and Western blot. Enzyme-linked immunosorbent and immunocytochemical analyses for the therapeutic gene demonstrated that transfected LLC cells secreted the protein into the medium. Exposure of the cells to 2 gray (Gy) gamma-rays reduced the time to reach the maximum expression level of the endostatin gene and also increased the amount of secreted endostatin protein (P<0.001). Biological activity of the endostatin was demonstrated by the inhibition of tube formation by human umbilical vein endothelial cells (HUVEC). Based on (3)H-thymidine incorporation, endostatin expression significantly depressed DNA synthesis in HUVEC and LLC cells compared to controls transfected with parental vector or no vector (P<0.005). In addition, radiation increased the efficiency of endostatin-mediated inhibition of both cell types over a 3-day period post-exposure (P<0.05 or less). Intratumoral injection of 100 small mu g pXLG-mEndo combined with 10 Gy radiation significantly delayed LLC tumor growth, especially when each modality was delivered twice (P<0.05 or less compared to all other groups). No toxicity was observed. These findings are very promising and suggest that endostatin therapy with a plasmid vector, such as pXLG-mEndo, may enhance the efficacy of radiotherapy for lung cancer.
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PMID:Radiation-enhanced endostatin gene expression and effects of combination treatment. 1577 88

Endostatin is an important endogenous inhibitor of neovascularization, which has been widely used in anti-angiogenesis therapy for cancer. To fully explore the potential of endostatin, we evaluated the anti-tumor efficacy of the combination of recombinant human endostatin adenovirus and low-dose gemcitabine in nude mice. We injected recombinant human endostatin adenovirus intratumorally plus a low dose of gemcitabine i.p. routinely. The combination treatment produced no side-effects, and resulted in marked suppression in tumor formation and growth of established human lung carcinoma xenografts in nude mice, with decreased microvessel density and increased apoptosis percentage. Our data support the idea of synergistic anti-tumor properties of endostatin plus low-dose chemotherapy against human lung cancer in vivo.
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PMID:Synergistic anti-tumor effect of recombinant human endostatin adenovirus combined with gemcitabine. 1584 21

Endostatin (ED) is a carboxyl-terminal fragment of type XVIII collagen with a strong anti-angiogenic activity. The purpose of this study is to determine the effect of ED gene transfer into lung cancer cells on in vivo tumor growth in a murine model. The murine lung cancer cell line, Lewis Lung Carcinoma (LLC), was transfected with ED gene to express and secrete ED. After clones were selected to secrete ED, several stable transfectants with ED gene (LLC/ED) and control transfectants (LLC/Mock) were established. In vitro proliferation of these transfectants demonstrated similar growth speed. In contrast to previous reports, in vivo subcutaneous tumorignecity of LCC/ED transfectants was significantly greater than that of LLC/Mock transfectants. Immunohistochemical staining analysis demonstrated that ED gene transfer induced angiogenesis, suggesting coinduction of another gene implicated for neovascularization. As expected, LLC/ED transfectants secreted not only ED but also vascular endothelial growth factor (VEGF) to a much greater degree than LLC/mock transfectants. Interestingly, culture supernatants of LLC/ED cells enhanced in vitro proliferation of human umbilical vein endothelial cells (HUVEC) to a much greater degree than those of LLC/Mock cells. These results indicate that ED gene transfer in murine lung carcinoma cells induces VEGF secretion, resulting in enhancement of in vivo tumorigenecity in the murine model. More attention should be paid for ED gene therapy into lung cancer cells since it may influence other proteins secretion, which upregulates angiogenesis.
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PMID:Endostatin gene transfer in murine lung carcinoma cells induces vascular endothelial growth factor secretion resulting in up-regulation of in vivo tumorigenecity. 1587 83


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