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)

Angiogenesis is in part responsible for tumor growth and the development of metastasis. Radiolabeled angiongenesis inhibitors would be useful to assess tumor microvasculature density. Colchicine (COL), a potent antiangiogenic agent, is known to inhibit microtubule polymerization and cell arrest at metaphase. This study aimed to develop 99mTc-labeled COL (EC-COL) using ethylenedicysteine (EC) as a chelator to assess tumor microvascular density. EC was conjugated to trimethylcolchicinic acid using N-hydroxysuccinimide and 1-ethyl-3-dimethylaminopropyl carbodiimide as coupling agents with a yield of 50-60%. In vivo stability was analyzed in rabbit serum at 0.5-4 h. Tissue distribution and planar imaging studies of [99mTc]EC-COL were evaluated in breast tumor-bearing rats at 0.5, 2 and 4 h. The data was compared to that using [99mTc]EC (control). The radiochemical yield of [99mTc]EC-COL was greater than 95%. [99mTc]EC-COL was stable in rabbit serum. In vivo biodistribution of [99mTc]EC-COL in breast tumor-bearing rats showed increased tumor-to-blood (0.52+/-0.12 to 0.72+/-0.07) and tumor-to-muscle (3.47+/-0.40 to 7.97+/-0.93) ratios as a function of time. Conversely, tumor-to-blood values showed a time-dependent decrease with [99mTc]EC over the same time period. Planar images confirmed that the tumors could be visualized clearly with [99mTc]EC-COL from 0.5 to 4 h. [99mTc]EC-COL may be useful to assess antiangiogenic and therapeutic effects during chemotherapy.
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PMID:Synthesis of [99mTc]ethylenedicysteine-colchicine for evaluation of antiangiogenic effect. 1050 19

The effects of the angiogenic inhibitors endostatin, angiostatin, and TNP-470 on tumor growth dynamics are experimentally and theoretically investigated. On the basis of the data, we pose a quantitative theory for tumor growth under angiogenic stimulator/inhibitor control that is both explanatory and clinically implementable. Our analysis offers a ranking of the relative effectiveness of these inhibitors. Additionally, it reveals the existence of an ultimate limitation to tumor size under angiogenic control, where opposing angiogenic stimuli come into dynamic balance, which can be modulated by antiangiogenic therapy. The competitive influences of angiogenically driven growth and inhibition underlying this framework may have ramifications for tissue size regulation in general.
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PMID:Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. 1051 81

Angiogenesis is required for tumor formation. Several studies have demonstrated that tumor angiogenesis is regulated by a balance between proangiogenesis and antiangiogenesis factors and that this balance varies in different organ environments. To investigate whether expression of an angiogenesis inhibitor by cancer cells could alter this balance and prevent tumor formation in different organ environments, we engineered stable transfectants from RenCa mouse renal carcinoma cells and SW620 human colon carcinoma cells to constitutively secrete a mouse endostatin protein with c-myc and polyhistidine (His) tags. Production and secretion of the endostatin-c-myc-His fusion protein by endostatin-transfected cells were confirmed by immunofluorescence staining and Western blot analysis. The endostatin transfectants and control transfectants, stably transfected with a control plasmid, had similar in vitro growth rates compared with their parental cell lines. Conditioned medium from endostatin-transfected cells inhibited human umbilical vein endothelial cell proliferation by 36-51% compared with conditioned medium from control cells. After inoculation into mice, flank tumors from endostatin-transfected cells were 73-91% smaller than flank tumors from control cells after 3 weeks. Inoculation of a cell mixture containing 25% endostatin-transfected cells and 75% control cells resulted in inhibition of flank tumor formation as effective as after inoculation of 100% endostatin-transfected cells. Formation of lung metastases by RenCa endostatin-transfected cells and formation of liver metastases by SW620 endostatin-transfected cells were dramatically inhibited compared with formation of metastases by control cells. These findings demonstrate that endostatin can inhibit tumor formation in different organ environments and that gene delivery of endostatin into even a minority of tumor cells may be an effective strategy to prevent progression of micrometastases to macroscopic disease.
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PMID:Mouse endostatin inhibits the formation of lung and liver metastases. 1062 20

Angiogenesis, the formation of new blood vessels from existing capillaries, is critical for tumors to grow beyond a few in size. Tumor cells produce one or more angiogenic factors including fibroblast growth factor and vascular endothelial growth factor. Surprisingly, antiangiogenic factors or angiogenesis inhibitors have been isolated from tumors. Some angiogenesis inhibitors, such as angiostatin, are associated with tumors while others, such as platelet-factor 4 and interferon-alpha are not. Endostatin, a C-terminal product of collagen XVIII, is a specific inhibitor of endothelial cell proliferation, migration and angiogenesis. The mechanism by which endostatin inhibits endothelial cell proliferation and migration is unknown. Endostatin was originally expressed in a prokaryotic system and, late, in a yeast system, thanks to which it is possible to obtain a sufficient quantity of the protein in a soluble and refolded form to be used in preclinical and clinical trials.
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PMID:Endostatin: a promising drug for antiangiogenic therapy. 1066 57

Endostatin, an inhibitor of angiogenesis and tumor growth, was identified originally in conditioned media of murine hemangioendothelioma (EOMA) cells. N-terminal amino acid sequencing demonstrated that it corresponds to a fragment of basement membrane collagen XVIII. Here we report that cathepsin L is secreted by EOMA cells and is responsible for the generation of endostatin with the predicted N-terminus, while metalloproteases produce larger fragments in a parallel processing pathway. Efficient endostatin generation requires a moderately acidic pH similar to the pericellular milieu of tumors. The secretion of cathepsin L by a tumor cell line of endothelial origin suggests that this cathepsin may play a role in angiogenesis. We propose that cleavage within collagen XVIII's protease-sensitive region evolved to regulate excessive proteolysis in conditions of induced angiogenesis.
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PMID:Secreted cathepsin L generates endostatin from collagen XVIII. 1071 19

We examined the effect on tumor growth, vessel morphology, and expression of angiogenic factors of combining radiotherapy and antiangiogenesis in the human glioblastoma line U87 grown in the flank or intracranially in the nude mouse. The antiangiogenic agent TNP-470 was given 6.7 mg/kg s.c. daily on day 1-7 starting 1 week after transplantation. Irradiation (IR), 10 Gy x 1, was administered on day 7. A series of tumors were excised 8 and 48 h after the end of treatment. The vascular morphology was evaluated in CD31 immunostained cryosections and by electron microscopy, and the pattern of expression of angiogenic factors (mRNA and protein) was quantitatively analyzed by phosphorimaging of Northern blots and Western blots. Significant inhibition of s.c. flank tumor growth relative to untreated controls was achieved by monotherapy with both TNP-470 (P < 0.001) and IR (P < 0.001). A significant enhancement of this effect was obtained by combining TNP-470 and IR (P < 0.05). We saw no effect of TNP-470 either alone or in addition to the effect of IR on the survival of mice with intracranial tumors. CD31 immunostaining of s.c. tumors showed acute endothelial swelling and luminal protrusion in irradiated tumor vessels but never in tumors pretreated with TNP-470, and not in the untreated controls. The vessel density (Chalkley point counts) was unchanged by TNP-470 therapy. In the TNP-470-treated tumors, we observed a distinct broadening of the endothelial basement membrane by an approximately 400-700-nm-thick electron-dense yet uncharacterized fibrillar material. TNP-470 treated tumors +/- IR also had a significantly increased mRNA expression of angiopoietin-1, whereas angiopoietin-2, vascular endothelial growth factor and basic fibroblast growth factor mRNA were unchanged by the treatments. In conclusion, TNP-470 significantly enhanced the tumor effect of ionizing IR, and our findings strongly indicate that acute microvascular damage after IR is effectively prevented by concurrent TNP-470 treatment. A significant up-regulation of angiopoietin-1 seems to play a role in this protective mechanism, which as yet is not fully elucidated.
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PMID:Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. 1074 23

Gene therapy represents a possible alternative to the chronic delivery of recombinant antiangiogenic proteins to cancer patients. Inducing normal host tissues to produce high circulating levels of these proteins may be more effective than targeting antiangiogenic genes to tumor tissue specifically. Previously reported gene therapy approaches in mice have achieved peak circulating endostatin levels of 8-33 ng/ml. Here we report plasma endostatin levels of 1770 ng/ml after administration of a recombinant adenovirus. Growth of MC38 adenocarcinoma, which is relatively resistant to adenoviral infection, was inhibited by 40%. These findings encourage gene delivery approaches that use the host as a "factory" to produce high circulating levels of antiangiogenic agents.
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PMID:Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice. 1074 12

Ovarian cancer is the leading cause of fatality among gynecological malignancies. Ovarian cancer growth is angiogenesis-dependent, and an increased production of angiogenic growth factors such as vascular endothelial growth factor is prognostically significant even during early stages of the disease. Therefore, we investigated whether antiangiogenic treatment can be used to inhibit the growth of ovarian cancer in an experimental model system. Mouse angiostatin (kringle 1-4) and endostatin were expressed in yeast. Purified angiostatin and endostatin were then used to treat established ovarian cancers in athymic mice. These studies showed that both angiostatin and endostatin inhibited tumor growth. However, angiostatin treatment was more effective in inhibiting ovarian cancer growth when compared with endostatin in parallel experiments. Residual tumors obtained from angiostatin- and endostatin-treated animals showed decreased number of blood vessels and, as a consequence, increased apoptosis of tumor cells. Subsequently, the efficacy of a combined treatment with angiostatin and endostatin was investigated. In the presence of both angiostatic proteins, endothelial cell proliferation was synergistically inhibited. Similarly, a combination regimen using equal amounts of angiostatin and endostatin showed more than additive effect in tumor growth inhibition when compared with treatment with individual angiostatic protein. These studies demonstrate synergism between two angiostatic molecules and that antiangiogenic therapy can be used to inhibit ovarian cancer growth.
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PMID:Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. 1078 83

The angiogenesis inhibitor endostatin is a 20 kDA C-terminal fragment of collagen XVIII, a proteoglycan/collagen found in vessel walls and basement membranes. The endostatin fragment was originally identified in conditioned media from a murine endothelial tumor cell line. Endostatin inhibits endothelial cell migration in vitro and appears to be highly effective in murine in vivo studies. The molecular mechanisms behind the inhibition of angiogenesis have not yet been elucidated. Studies of the crystal structure of endostatin have shown a compact globular fold, with one face particularly rich in arginine residues acting as a heparin-binding epitope. It was initially suggested that zinc binding was essential for the antiangiogenic mechanism but later studies indicate that zinc has a structural rather than a functional role in endostatin. The generation of endostatin or endostatin-like collagen XVIII fragments is catalyzed by proteolytic enzymes, including cathepsin L and matrix metalloproteases, that cleave peptide bonds within the protease-sensitive hinge region of the C-terminal domain. The processing of collagen XVIII to endostatin may represent a local control mechanism for the regulation of angiogenesis.
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PMID:Collagen XVIII/endostatin structure and functional role in angiogenesis. 1088 79

Both chemotherapy and chimeric anti-CD20 monoclonal antibodies are effective agents against B-cell non-Hodgkin lymphoma (NHL). However, patients achieving remission are at risk of relapse. To evaluate the effect of the antiangiogenic drug endostatin used alone and after the administration of cyclophosphamide (CTX) or the anti-CD20 antibody rituximab, we generated a new model of human NHL by transplanting Namalwa cells intraperitoneally into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. First, we determined the most effective treatment schedule for the drugs assessed. When administered alone, CTX (3 courses of 75 mg/kg of body weight given intraperitoneally), rituximab (3 courses of 25 mg/kg given intraperitoneally), and endostatin (5 courses of 50 microg given subcutaneously) delayed tumor growth, and CTX was the most effective in controlling bulky disease. When given after chemotherapy or immunotherapy, endostatin effectively induced tumor stabilization. When mice given CTX or rituximab on days 3, 5, and 7 after transplantation were randomly assigned to receive endostatin or phosphate-buffered saline on days 15 to 19, tumor growth was prevented in endostatin-treated mice as long as the drug was administered. Furthermore, administration of endostatin on days 25 to 29 after tumor regrowth still induced significant tumor regression, whereas CTX and rituximab were not effective. The specific antiangiogenic action of endostatin was confirmed by in vitro and in vivo studies indicating that the drug inhibited proliferation and induced apoptosis of endothelial (but not of NHL) cells. In conclusion, sequential administration of chemotherapy and endostatin seems promising for treating bulky NHL, and the less toxic sequential administration of rituximab and endostatin is promising for treating limited disease. (
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PMID:Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-grade non-Hodgkin lymphoma. 1089 63


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