Angiostatin


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Angiostatin - Wikipedia

ANG exhibits profound inhibition of endothelial cell proliferation and migration in vitro and angiogenesis in vivo 5. Systemic administration of recombinant ANG inhibited angiogenesis and increased the apoptotic rate in several tumor models followed by tumor regression 6. The formation of ANG implicates metalloproteinases or serine proteinases produced by tumor cells 7 or by tumor-infiltrating macrophages 8. However, the molecular mechanisms of ANG treatment in vivo remain ill defined.

Therefore, monitoring of antiangiogenic approaches with functional imaging and histomorphometric analyses are desirable to deliver information about physiologic effects caused by these therapeutic modalities. To provide a noninvasive, functional relevant measure of angiogenesis and to obtain functional data in animals and humans, MRI, CT, ultrasonography, optical imaging, and PET have been proposed 9.

Especially PET using H 2 15 O provides a quantitative measure of tissue perfusion—that is, blood flow and blood volume in tumors 9. The aim of this study was to evaluate the effects of hANG gene transfer on tumor growth and changes in perfusion or blood volume relating in vivo measurements with PET to immunohistochemistry and gene expression analysis. The hANG protein consists of amino acids, including the first 4 kringle structures. Secretion of hANG protein from selected clones into cell culture media was verified by Western blots.

Conditioned medium was produced by culture of 10 6 transfected Morris hepatoma cells in Optimem medium Invitrogen for 48 h. Coculture experiments were done in triplicate in 2 independent experiments. All animal studies were performed in compliance with the national laws relating to the conduct of animal experimentation. The in vitro doubling time of the cell lines used was A transmission scan was done for 10 min before tracer administration with 3 rotating germanium pin sources to obtain cross sections for attenuation correction. After iterative reconstruction ordered-subsets expectation maximization; 8 subsets, 16 iterations , dynamic PET data were evaluated following definition of volumes of interest VOIs as described earlier using the PMOD software package Irregular ROIs were drawn manually.

Perfusion studies using H 2 15 O were evaluated using a 1-tissue-compartment model For the input function, we used the mean value of the VOI data obtained from the heart. ROIs were defined at 3—6 s after bolus injection in at least 3 consecutive slices 2. This approach was based on the findings of Ohtake et al.

The heart weight and heart volume of a g rat are 1. The 68 Ga-DOTA-albumin uptake was expressed as the mean standardized uptake value SUV between 10 and 15 min after injection when the time—activity curve reaches a plateau. Negative controls were performed using control immunoglobulin or omission of the primary antibody. A protein with a molecular weight of 56 kDa was identified in cell culture medium of hANG-overexpressing cells Fig. A Northern blot. B Western blot. Representative blots are shown.

A Proliferation acid-soluble and acid-insoluble fractions of thymidine uptake. B Apoptosis. After inoculation of tumor cell suspensions, we examined growth of WT- and hANG-MHA tumors in rats, including histologic analysis of proliferation, necrosis, apoptosis, and the content of oxidative stress inducing cells in these tumors.

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Angiostatin Antibody (79735) - Kringle 1-3

Given that hANG has been described as a strong inhibitor of angiogenesis, we expected significant differences in tissue perfusion and blood volume in tumors overexpressing angiostatin. The ratios for albumin showed similar changes 0. Microvessel density is 2—3 times higher in the periphery in comparison with the center.

What does angiostatin mean?

In addition, the mean number of blood vessels was significantly increased in hANG- Immunohistomorphometric analysis of vascularization in Morris hepatomas. Control immunoglobulin data not shown was used as negative controls. Immunoreactive areas were quantified by analyzing 5 hot spots per tumor. To assess general effects of hANG gene transfer on tumor cells in vitro and in vivo, the gene expression pattern was studied using gene arrays Table 1. Because transfer of selection markers such as the hygromycin gene and the selection procedure may cause changes in the genetic program, we analyzed the expression pattern in tumor cell lines as well as in explanted tumors of these cell lines.

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Gene transfer of antiangiogenic genes has been suggested as a new strategy of tumor therapy. Benefits of this therapeutic approach are the long-term expression of antiangiogenic genes, which is advantageous for the angiostatic character of most antiangiogenic therapies and the genetic stability of endothelium. Another advantage is local production of therapeutic agents at the tumor site, thereby preventing rapid degradation of therapeutic molecules in plasma. Furthermore, these results are in concert with recent reports showing that angiostatin inhibits cell proliferation and induces apoptosis in bovine aortic endothelial cells and HUVECs Similar results of tumor growth suppression were noted in mice bearing ANG-expressing hepatocellular carcinoma 18 or because of application of recombinant adeno-associated virus encoding ANG plus endostatin using an ovarian cancer cell model Our immunohistochemical analyses indicated decreased proliferation together with an increased apoptosis rate in these tumors Figs.

The angiogenesis inhibitor is not directly cytotoxic to tumor cells.


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Induction of apoptosis may be explained by diminished paracrine release of antiapoptotic factors and increased release of apoptotic factors from endothelial cells into tumor bed. H 2 15 O is perfectly suited for examining tumor tissue perfusion, because it is an inert and freely diffusible molecule not participating in metabolic processes at least during PET measurements 22 , 23 , whereas 68 Ga-DOTA-albumin, a tracer of the blood volume, persists in the intravascular space during PET studies.

The higher tumor-to-heart ratios for H 2 15 O as compared with albumin are explained by the different distribution of these tracers. The pharmacokinetic model assumes that K 1 is in agreement with blood flow if the extraction rate is high.

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For example, a value of 2 means that during equilibrium the radioactive concentration in tissue is twice as high compared with that in blood. Because WT- and hANG-expressing tumors did not differ in diameter, changes in tissue perfusion or blood volumes are not due to partial-volume effects. In addition, our PET data are in accordance with our histologic findings that microvessel density is also significantly increased in hANG-overexpressing hepatomas, whereas the fraction of larger vessels e.

Similar data were obtained with endostatin, where evidence for a dose-dependent biphasic change of tumor perfusion measured by H 2 15 O PET was found in a phase I clinical trial Lower doses of endostatin resulted in an increase of tumor blood flow, whereas a decrease of tumor blood flow was noted when intermediate or high doses were applied.

Improvement of perfusion and dose-dependent response on antiangiogenic agents has been explained by the hypothesis of a decrease in interstitial fluid pressure or normalization of tumor vasculature followed by diminished hypoxia Although it may be speculated that a normalization of tumor vasculature stimulates tumor proliferation, animal and clinical studies to date show no acceleration of tumor growth during antiangiogenic monotherapy despite tumor vessel normalization This corresponds to the higher microvessel density and the improvement of perfusion in these tumors.

Therefore, our results imply a better exchange of oxygen and nutrients as well as an improved removal of toxic metabolites from tumor tissue in hANG-overexpressing tumors followed by a decrease of hypoxia but without enhancing tumor growth.

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Changes in hypoxia may have multiple consequences for the tumor biology, such as promotion of genomic instability 28 and decreased secretion of tumor growth factors. The consequences of hypoxia probably depend on the tumor gene expression level and microenvironment. By Northern analysis, however, we have found no evidence that the tumor cells express angiostatin or other fragments of plasminogen data not shown. We now report that gelatinase A matrix metalloproteinase-2 , produced directly by the LLC-LM cells, is responsible for the production of angiostatin, which suppresses the growth of metastases in our original model.


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  8. Recently, in vitro studies of cancer cell lines have shown that a variety of enzymes can cleave plasminogen into fragments of plasminogen with a similar sequence and activity to that of the angiostatin protein we first described 1. However, none of these reports have identified the specific enzyme involved in the production of the biologically active angiostatin in the in vivo Lewis lung model in which angiostatin was first discovered nor have they demonstrated the production of angiostatin with identical sequence, composition, or biological activity to that which we first described.

    Here we present the first report of the production of biologically active angiostatin by tumor cells that correlates to the inhibition of tumor growth by tumor mass. Media were then collected, centrifuged, filtered 0. Substrate gel electrophoresis was conducted according to a modification 9 of the method of Herron et al.

    After electrophoresis, the gels were soaked in 2. After incubation, gels were stained for 15—30 min in 0. Bovine capillary EC were maintained and the inhibition assay was performed as described previously 1 , The medium was then replaced with 0. After 20 min of incubation, media and basic fibroblast growth factor bFGF were added to each well to obtain a final volume of 0.

    After incubation for 72 h, media were aspirated, and the cells were removed by trypsinization, resuspended in Hematall, and counted electronically with a cell counter. Following incubation, test samples or control samples serum-free control media not conditioned by cells but identically treated otherwise were applied to a lysine-Sepharose Amersham Pharmacia Biotech column that had been equilibrated with 50 m m phosphate buffer, pH 7. The column was reequilibrated with 50 m m phosphate buffer, pH 7.

    Samples were fractionated by elution with 0. Protein was eluted using a gradient of 0. Aliquots of each fraction were immediately concentrated by vacuum centrifugation, resuspended in H 2 O or phosphate-buffered saline, and tested for their ability to inhibit capillary EC proliferation stimulated by bFGF as described above. This mixture was then incubated with whole plasminogen as described above. Controls included a sample of LLC-CM incubated with human plasminogen under the same conditions but in the absence of the neutralizing antisera. Following the incubation with human plasminogen, samples from each of the treatment groups were fractionated over a lysine affinity column, followed by reverse phase HPLC chromatography as described above.

    The N-terminal sequence was determined by William S.

    Angiostatin Angiostatin
    Angiostatin Angiostatin
    Angiostatin Angiostatin
    Angiostatin Angiostatin
    Angiostatin Angiostatin
    Angiostatin Angiostatin

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