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1
Gogat, Karïn. "L'angiogenèse Oculaire : approche Fondamentale lors du Développement et Approche Thérapeutique." Paris 7, 2003. http://www.theses.fr/2003PA077215.
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Galaup, Ariane. "Inhibition de l'angiogénèse tumorale par transfert de gènes angiostatiques associés ou non à une chimiothérapie." Paris 7, 2003. http://www.theses.fr/2003PA077213.
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Drenberg, Christina Diane. "Angiostatic Regulators in Ovarian Cancer." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3557.
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Angiogenesis by either normal or neoplastic cells involves a delicate balance of both angiogenic and angiostatic regulators. In the ovary, normal physiological angiogenesis occurs around the developing follicle and corpus luteum in response to hormonal shifts. Interestingly, carcinomas arising from the ovary are usually highly vascularized and are commonly clinically observed to produce cyst fluids or ascites which contain both angiostatic and/or angiogenic regulators. However, in contrast to normal angiogenesis, angiogenesis associated with epithelial ovarian cancer usually produces aberrant vasculature that may promote neoplastic progression. Therefore, the ovary and ovarian cancers provide models to study the mechanisms governing the strict balance of angioregulators in both normal and tumor angiogenesis. While most studies to date have focused on angiogenic regulators for normal and aberrant angiogenesis, we investigated the potential for dysregulation of angiostatic regulators to contribute to the etiology of epithelial ovarian cancer. Therefore, in this study, we examined two angiostatic regulators, angiostatin and semaphorin 3F, in epithelial ovarian cancer.
Angiostatin, a cleavage product of the circulating zymogen plasminogen, was isolated from serum and urine of mice bearing a Lewis lung carcinoma and in vivo studies have demonstrated its potent angiostatic properties. Thus, we investigated the potential prognostic/diagnostic advantage of aberrant angiostatin expression with epithelial ovarian cancer. We found that urinary angiostatin, compared to other angioregulators in plasma or urine, could serve as an effective biomarker for early detection of epithelial ovarian cancer, especially when used in combination with cancer antigen 125. Additionally, urinary angiostatin correlated with both recurrent disease as well as successful tumor ablation further supporting its potential as a disease biomarker.
Alternative biological functions for the axon guidance molecule, semaphorin 3F, have been reported particularly in regard to angiogenesis, tumor progression and metastasis. However, the underlying mechanisms governing semaphorin 3F regulation and dysregulation remain unclear. Therefore, we first investigated the clinical relationship between semaphorin 3F expression and epithelial ovarian cancer progression. These immunohistological studies revealed that, similar to lung cancer, semaphorin 3F expression decreased with progression supporting a tumor suppressor-like role for semaphorin 3F. Additionally, we found that calcium, an essential cellular signaling molecule, could mediate transcriptional suppression of semaphorin 3F expression in a CREB-dependent manner.
Lastly, given the antagonistic relationship between semaphorin 3F and vascular endothelial growth factor, we sought to determine whether semaphorin 3F and vascular endothelial growth factor promoted opposing effects on a common downstream target. In the course of these studies we determined that telomerase is a novel molecular target of semaphorin 3F in ovarian cancer cells such that semaphorin 3F suppresses telomerase activity while vascular endothelial growth factor promotes telomerase activity. In addition, we found that the inverse relationship between semaphorin 3F and telomerase was mediated through transcriptional inhibition of the hTERT promoter by semaphorin 3F.
In conclusion, this research shows that dysregulation of the angiostatic regulators, angiostatin and semaphorin 3F, may contribute to the etiology of epithelial ovarian cancer. In the future, dysregulation of these and other angiostatic regulators may be exploited for therapeutic intervention or as biomarkers for early detection which would allow women more treatment choices and hopefully, reduce the mortality associated with this insidious disease.
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Veitonmäki, Niina. "Angiostatic mechanisms of endogenous angiogenesis inhibitors /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-555-7/.
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Chen, Chang-Hwa Mary 1971. "The effect of angiostatin on the endothelial cell cycle." Thesis, Massachusetts Institute of Technology, 1998. http://hdl.handle.net/1721.1/50431.
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Levchenko, Tetyana. "The role of angiomotin in angiogenesis /." Stockholm, 2003. http://diss.kib.ki.se/2004/91-7349-761-4/.
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Cnudde, Sara Elizabeth. "The x-ray crystallographic structures of the angiogenesis inhibitor angiostatin bound to a peptide from the group A streptococcal surface protein PAM and the metal-bound conantokins con-G and con-T[K7gamma]." Diss., Connect to online resource - MSU authorized users, 2007.
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8
Stefanutti, Erin. "ANGIOSTATIN LIKE PEPTIDES IN MILK: POTENTIAL DEVELOPMENT FOR DAIRY PRODUCTS CAPABLE OF CANCER PREVENTION." DigitalCommons@CalPoly, 2011. https://digitalcommons.calpoly.edu/theses/479.
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For the past 40 years, antiangiogenic approaches have been of major interest in the development of methods to cure and prevent cancer. Angiogenesis, the development of blood vessels from pre-existing vascularization, is essential for cancer growth and spread of metastasis through the delivery of nutrients and oxygen essential to sustain the metabolic activity of these malignant cells. Blocking access to blood will cause cancerous cells to assume a dormant state creating inactive micro-tumors innocuous to the host. Angiostatin, the internal fragment of the fibrinolytic zymogen plasminogen, has shown great potential in reducing cancer size and number of metastatic colonies in animal models. Owing to the success of these preliminary results angiostatin is currently on clinical trials. Plasminogen is known to be transferred from blood to milk during lactation. The objectives of this research were to: 1) investigate the ability of various proteases in cleaving plasminogen, both from human and bovine sources, and consequently release the angiostatin like fragment; 2) determine the anticancer activity of bovine angiostatin; 3) examine ability of the antiangiogenic fragment to survive digestion; 4) purify the fragment of interest through column chromatography. Production of angiostatin was tested through hydrolysis of plasminogen via Bacillus Polymyxa protease (or dispase I), elastase, lactic acid bacteria and Bacilli originated enzymes. Once proteases capable of angiostatin like peptide production were identified, and sequence analysis of the fragments obtained conducted to confirm that bovine angiostatin was indeed produced, ability of angiostatin, both human and bovine, in inhibiting malignant melanoma as well as colon cancer cells was evaluated in vitro. From the results obtained we can confirm that bovine angiostatin inhibitory activity on cancerous cells is similar to that observed for human angiostatin. Analysis of bovine angiostatin survival through in vitro human digestion model was also examined. Results show good possibility of angiostatin surviving digestion, even if confirmation of these results is required through further in vivo studies. Additionally, digestive enzymes such as trypsin and α-chymotrypsin showed ability in cleaving plasminogen directly to release a 25kDa fragment. Knowing that each kringle has some degree of anticancer activity it would be of interest to further study the possibility of angiostatin related fragments to be produced during milk digestion. Finally, affinity chromatography through L-lysine used to purify human angiostatin resulted to be an adequate method for bovine angiostatin purification. Preliminary results obtained from this study open a new area worth investigating to uncover the potential of using bovine angiostatin in the development of novel food products capable of cancer prevention.
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Griscelli, Frank. "Utilisation d'adénovirus recombinants pour le ciblage de l'expression de gènes thérapeutiques : application dans le domaine de la cardiologie et de la cancérologie." Paris 11, 1999. http://www.theses.fr/1999PA11T015.
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La multiplication des protocoles cliniques laisse espérer que la thérapie génique fera partie dans l'avenir de l'arsenal thérapeutique pour le traitement des maladies acquises comme les cancers, même si un long chemin reste à parcourir pour mettre au point des vecteurs totalement sûrs et efficaces. Les adénovirus recombinants sont actuellement les vecteurs de choix très utilisés pour cette approche, car ils sont capables de délivrer l'information génétique dans un grand nombre de tissus. Afin d'éviter l'expression ubiquitaire du transgène dans tous ces tissus, nous montrons qu'il est possible de cibler l'expression du transgène à l'aide d'adénovirus recombinants, dans un seul type cellulaire, ce qui permettra d'utiliser ces vecteurs avec une plus grande sécurité. Nous montrons que l'utilisation de promoteurs spécifiques de tissus est une des approches possibles pour cibler l'expression d'un transgène. Nous avons pris l'exemple du promoteur de l'isoforme 2v de la chaîne légère de la myosine pour valider cette approche. Deux adénovirus recombinants ont été construits contenant le gène de la B-galactosidase mis sous contrôle de la version longue (2100 bp) ou courte (250 bp) du promoteur cardiaque. Nous montrons que ces deux promoteurs conservent leur spécificité d'origine in vivo après injection intracardiaque du virus et in ovo après injection systémique du virus dans des embryons de poulets, mais que leurs activités restent faibles par rapport à celles observées avec les promoteurs viraux. Cette voie semble être néanmoins intéressante pour le ciblage de l'expression de gènes. Notre position au sein du centre anticancéreux de Villejuif nous a fait nous intéresser au développement de la thérapie génique anti-angiogénique dans la lutte anticancéreuse. C'est une voie prometteuse car elle vise à inhiber le développement et la dissémination tumorale. De plus cette thérapeutique est adaptée à tous les cancers pour transformer une tumeur active, maligne en tumeur "dormante" et bénigne. Nous avons construit deux adénovirus recombinants qui codent pour l'angiostatine humaine, un fragment amineterminal du plasminogène (résidu 1-333) ou pour l'ATF murin, un fragment amine-terminal de l'urokinase (résidu 1-135), qui ont in vivo et in vitro respectivement la propriété d'inhiber la prolifération de cellules endothéliales activées et les cellules endothéliales ayant acquis un phénotype migratoire. Nous montrons que le transfert du gène de l'angiostatine et de l'ATF dans plusieurs modèles de xénogreffes murins entraîne un arrêt significatif de la croissance tumorale qui est corrélé avec une importante inhibition de la vascularisation péri-tumorale et intra tumorale. Nous montrons également que le transfert du gène de l'ATF murin permet d'inhiber in vitro la migration des cellules tumorales et in vivo la formation de métastases dans deux modèles expérimentaux murins, un carcinome pulmonaire et un carcinome du côlon. Avec cette thérapie, seules lès cellules endothéliales angiogéniques sont affectées, alors que les cellules endothéliales vasculaires ne le sont pas, ce qui laisse présager de l'absence de toxicité vasculaire de cette approche.
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Raisler, Brian. "Adeno-associated virus type-2 mediated expression of pigmented epithelium derived factor or kringles 1-3 of angiostatin reduced neovascular retinopathies." [Gainesville, Fla.] : University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0002385.
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Sangaletti, Laila Abicair. "Estudo dos efeitos da LDL (-) na angiogênese modelos in vitro e in vivo." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-29092017-104111/.
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Diversas doenças estão associadas com a formação de novos vasos a parti vasos pré-existentes, ou angiogênese. Dentre elas está a aterosclerose (Griffioen & Molema, 2000). Pesquisas recentes demonstram que a hipercolesterolemia, que têm um papel importante na fisiologia da aterosclerose, também pode prejudicar a ação de fatores angiogênicos (Jang et.al., 2000). A hipercolesterolemia que é decorrente de aumento de LDL no plasma ocasiona um aumento no tempo de permanência desta partícula na circulação (Yasunobu, 2001). Contudo, a LDL pode sofrer modificação na circulação, dando origem a uma subfração mais eletronegativa da LDL, a LDL (-). A LDL (-) pode prejudicar cada etapa da angiogênese, desregulando a função endotelial (Tai et. al., 2006). Em nosso estudo, vimos que apesar da LDL (-) ter estimulado a miga celular, esta partícula inibiu a formação de túbulos in vitro. A LDL (-) não foi capa afetar a angiogênese in vivo.A large number of diseases is associated with formation of new blood vessels out of pre-existing capillaries, or angiogenesis. These diseases include the atherosclerosis (Griffioen & Molema, 2000). Resents researches demonstrate that the hypercholesterolemia, that have a important role in the physiology of the atherosclerosis, can impaired the angiogenesis (Jang et. al., 2000) . The hypercholesterolemia that is decurrente of high levels of LDL in the plasma causes an increase in the time of permanence this particle in the circulation (Yasunobu, 2001). However, the LDL can to suffer modification in the circulation, giving rise to a subfration more eletronegative from LDL, the LDL (-). The LDL (-) could impair each one of the steps of the angiogenesis, thereby dysregulating endothelial function (Tai et. al., 2006). In our study, see that despite the LDL (-) have stimulated the cell migration, this particle inhibited the Tube formation in vitro. The LDL (-) didn\'t affect the angiogenesis in vivo.
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Stalin, Jimmy. "Contribution à l'étude du rôle de CD146 soluble dans les pathologies angiogéniques." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5080.
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Parmi les pathologies ischémiques, l'ischémie aiguë des membres inférieurs (IAMI) fait l'objet de nombreuses recherches ayant pour but une meilleure compréhension des mécanismes physiopathologiques et la mise au point de thérapies efficaces. Les cellules progénitrices endothéliales (PEC) participent à la régénération des vaisseaux lors d'événements ischémiques. En pathologie tumorale, la résistance aux traitements disponibles pousse la recherche à trouver de nouvelles cibles thérapeutiques. Depuis plusieurs années, notre équipe travaille sur la molécule CD146. Il a été démontré que la forme soluble de CD146 est une molécule angiogénique impliquée en physiologie et en pathologie. Notre travail a donc consisté à étudier le mécanisme d'action de cette molécule en pathologies. Les travaux de cette thèse comportent plusieurs axes :Un premier dans lequel l'étude des modulations des effets de CD146 soluble sur les PEC a permis de mettre en évidence son récepteur, l'angiomotine. La seconde partie du travail a porté sur l'étude des effets d'un prétraitement par CD146 soluble de PEC sur un modèle d'IAMI chez la souris. In vitro et in vivo, CD146 soluble augmente les propriétés angiogéniques et la viabilité des PEC.Enfin, la troisième partie des travaux réalisés durant ma thèse a porté sur le rôle de sCD146 en pathologie cancéreuse. Nous avons développé des modèles de xénogreffes decellules cancéreuses nous permettant d'examiner les effets de CD146 soluble sur la croissance tumorale par l'injection de la molecule. Les résultats obtenus montrent que CD146 soluble augmente la croissance et la vascularisation tumoraleDiseases with angiogenic component such as ischaemic pathologies and cancer have a high incidence. Among ischaemic pathologies, the acute ischaemia of the lower limbs made the object of many research having for goal a better comprehension of the physiopathological mechanisms and the development of effective therapies. The endothelial progenitor cells (EPC) take part in the regeneration of the vessels during ischaemia. In tumoral pathology, resistance to available treatments pushes research to find new therapeutic targets. For several years, our team has worked on CD146 molecule. It was shown that the soluble form of CD146 is an angiogenic factor involved in physiology and pathology. Our work thus consisted in studying the mechanism of action of this molecule in pathologies. Work of this thesis comprises several axes: A first in which the study of the modulations of the effects of soluble CD146 on EPC made it possible to highlight its receptor, angiomotin protein. The second part of the work concerned the study of the effects of a pretreatment by soluble CD146 on EPC on a model of IAMI in mouse. In vitro and in vivo, soluble CD146 increases the angiogenic properties and the viability of the EPC. Lastly, the third part of the work completed during my thesis concerned the role of sCD146 in cancerous pathology. We developed xenograft models of cancer cells allowing us to examine the effects of soluble CD146 on the tumor growth by the injection of this molecule. The results obtained show that soluble CD146 increases tumor growth and vascularization
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Khoueir, Paul. "Effets des polyphénols du thé vert et de la radiothérapie sur la progression et la résistance tumorale dans un modèle in vivo de glioblastome." Thèse, 2004. http://hdl.handle.net/1866/15763.
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Chen, Wen-Yu, and 陳汶妤. "sturctural and functional studies on angiostatin." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/18006184663633615370.
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碩士國立成功大學
生物化學研究所
89
Angiogenesis plays a fundamental role in many physiological and pathological processes, such as the tissue or organ regeneration, embryonic development, tumor growth and metastastases. Angiostatin, a 38kD protein, is an inhibitor of angiogensis. It is also an internal fragment of plasminogen comprised of the first four triple disulfide-linked kringle structure. Since the first isolation of the angiostatin protein by Dr. Folkman’s group, numerous researches have been conducted on this topic. Many studies have demonstrated that angiostatin containing K1-4 fragment isn’t the most powerful inhibitor of angiogenesis. In endothelial cell migration assay, the reduced kringle 5 domain fragment achieves the highest inhibition; the kringle 1 domain or kringle 1-3 fragment has the lowest activity of inhibition. In endothelial cell proliferation assay, the kringle 5 domain alone demonstrates highest level of inhibition; the kringle 4 domain has lower level of inhibition. It has also been shown that when disulfide bond of plasmin kringle 5 is reduced, the more potent angiostatin can be generated by enzyme catalization. Therefore multiple kringle fragments of angiostatin have different inhibitory effect on the angiogenesis. In this thesis, we want to understand the effect of the different levels of disulfide bridge disruption on the anti-angiogenic activity. We selected three specific cleavage sites in kringle 3, kringle 4 and kringle 5, i.e. k3316, k3328, k3333in kringle 3; k4418, k4430 and k4435 in kringle 4; and, k5524, k5536 and k5541 in kringle 5 to generate various fragments of plasminogen. In addition, we also prepare three fragments with intact kringle, i.e. K3354(wt), K4443(wt)and K5548(wt). Currently, we have successfully expressed twelve different length fragments of angiostatin using the Pichia pastoris expression system and tested their anti-angiogenic activity by Calf Pulmonary Artery Endothelial Cell (CPAE). In endothelial cell migration assay, the plasminogen fragments with reduced disulfide bridge had higher inhibitory effect then that of fragments with intact kringle structure, suggesting that the breakage of disulfide linkage in kringle is the prerequisite for the generation of potent angiostatin. In the proliferation assay, we found that K4418 and K4430 had higher inhibitory activity then other fragments suggesting the potential role of K4. In HPLC analysis, one or two peaks (RT19 and RT22) were identified for each fragment.
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Hsieh, Rong-Chung, and 謝榮忠. "The relationship between the production of angiostatin and plasminogen metabolism." Thesis, 1997. http://ndltd.ncl.edu.tw/handle/75673403854647605414.
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碩士國立成功大學
生物化學研究所
85
The discovery of endogeneous angiogenic inhibitor, angiostatin, in 1994 was a great shocking to biological medicine at that time because it provided a more resonable explanation for a surgical phenomenon: " why the surgical resection of the primary tumor can be followed by a rapid growth of metastatic secondary tumor ? ". Angiostatin, a 38KDa protein isolated and characterized by O''Reilly et al., is produced by the transplantable murine Lewis lung carcinoma ( LLC-LM ) growthing in syngeneic mice. This fragment strongly inhibits the bFGF-induced capillary endothelial cell proliferation and the bFGF-induced angiogenesis in pocket assay. Microsequence analysis of angiostatin reveals greater than 98% identity to an internal fragment of plasminogen which includes the first four kringle domains. However, there are several important questions remain to be answered：1). Which cells can degrade plasminogen into angiostatin ? 2). what pathway(s) is(are) responsible for the generation of angiostatin ?.Kringle 1-3 prepared by limited pancreatic elastase digestion of human plasminogen isolated from human plasma could inhibit the bFGF-induced bovine carotid artery endothelial cell proliferation. Further, in order to generate purified angiostatin for bioactivity analyses, human plasminogen was incubated with LLC-LM. The conditioned medium was applied to a lysine-sepharose column and the elute fractions were further purified by electrophoresis to get purified proteins. By western blot and N-terminal amino acid sequencing analysis, four plasminogen fragments (20KDa, 38KDa, 42KDa,and 55KDa fragments) with an N-terminus begining at kringle 1 were isolated. All these fragments could inhibit the bFGF-induced bovine carotid artery endothelial cell proliferation. Thus both the 38KDa and 42KDa fragments may be considered as angiostatin.By analyzing the N-termini of these plasminogen fragments, it was suggested that their N-termini might be generated by plasmin. Experimental data also revealed that plasmin inhibitor (aprotinin) but not elastase inhibitor (a1-antitrypsin) could inhibit LLC-LM to degrade plasminogen into these fragments, and in the solutions of pH7.0 to 10.5, plasmin could degrade heavy chain into different fragments with molecular weight range between 36KDa and 63KDa. The plasmin activity could be detected only when LLC- LM was incubated with plasminogen, and the conditioned serum- free culture medium of LLC-LM degraded plasminogen similarity as LLC-LM. These data suggested that LLC-LM could secrete plasminogen activators to activate plasminogen into plasmin, and by plasmin, plasmin and plasminogen could be degraded into angiostatin. In addition, several normal cells and tumor cell lines were screened for angiostatin production.It has been suggested that angiostatin may also be produced by macrophage which contains many degradative enzymes including elastase, or by the vascular endothelial cells under the infulence of paracine factors secreted by the tumor cells. But our data revealed that with or without the influence of LLC-LM, macrophage could not produce angiostatin；however, the bovine carotid artery endothelial cells could produce less angiostatin regardless the influence of LLC-LM, probably due to its ability to secrete urokinase-type plasminogen activator (u-PA) to activate plasminogen into plasmin.In order to identify which cells can directly or indirectly degrade plasminogen into angiostatin by immunoprceipitation, rabbit anti-kringle 1-3 polyclonal antibody was prepared.
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Chen, Ya-Huey, and 陳雅惠. "Delineation of the molecular mechanism of angiogenesis mediated by angiostatin." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/33763217790068908854.
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博士國立成功大學
基礎醫學研究所
95
Angiostatin, a circulating inhibitor of angiogenesis, is an internal fragment of plasminogen that contains the first four kringle domains (K1-4) of plasminogen. Further studies showed that angiostatin-like molecules consisting of only the first three kringle domains (K1-3) was more antiangiogenic than K1-4, and that there is the existence of a naturally occurring isoform, K1-4.5. It is not clear whether different isoforms of angiostatin utilized similar or distinct pathways to mediate anti-angiogenesis. We first examined the signaling pathway mediated by proapoptotic angiostatin, K1-4. Inductions of p53-mediated intrinsic and FasL-mediated extrinsic death signaling pathways are involved in anti-angiogenic action of K1-4. We then compared the signaling pathways and mRNA expression profiles modulated by K1-3, K1-4, and K1-4.5. Although the extent of anti-angiogenic potency might vary among different isoforms, K1-3 or K1-4.5 shared similar death pathways with those mediated by K1-4. Moreover, all three forms of angiostatin induced a similar subset of mRNA expression with some variations. The common pathways shared by K1-3, K1-4, and K1-4.5 might be used as new therapeutic targets for anti-angiogenic therapy. Among the deregulated genes, the expression of E-selectin, an adhesion molecule, was not only induced by all isoforms but also previously implicated in antiangiogenic action of endostatin. Since K1-3 had the highest ability to induce E-selectin, we then used K1-3 to study the underlying mechanism responsible for the K1-3-induced expression of E-selectin. RT-PCR and western blotting analyses confirmed the time-dependent increase of E-selectin mRNA and protein induced by K1-3. Moreover, subcellular fraction and immunofluorescence microscopy confirmed the predominant presence of K1-3-induced E-selectin in lipid raft. Promoter driven reporter assays demonstrated both AP1 and Ets-1 binding sites on the E-selectin promoter were crucial for the induction of E-selectin. EMSA and ChIp assays confirmed the in vitro and in vivo binding of AP1 complex and Ets-1. Repression of JNK, a N-terminal kinase for c-Jun, significantly suppressed the K1-3 induced expression of E-selectin, suggesting a requirement of JNK activation for induction of E-selectin. The positive involvement of E-selectin in the anti-angiogenic action of K1-3 was, respectively, confirmed by overexpression and knockdown of E-selectin. In summary, we have identified the E-selectin as a novel target for the antiangiogenic action of angiostatin.
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Chen, Ying-Han, and 陳英翰. "Study on the Anti-Tumorigenic Effect of Human Angiostatin Transfected Tumor cells." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/67356657978663638896.
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碩士國立成功大學
生物化學研究所
89
Abstract Tumor growth and metastasis are angiogenesis dependent. Angiogenesis is a multi-step process consisting of degradation of basement membrane at the post —capillary venule, migration of endothelial cells to the tumor, proliferation of endothelial cells, canalization and branching, and formation of new basement membrane and blood vessels. The factors which involve in the processing of angiogenesis could regulate new vascular formation and affect tumor growth. In 1994, Dr. Folkman and his colleagues have identified a protein which could inhibit angiogenesis of lung metastasis of a murine Lewis lung carcinoma and which was named “Angiostatin.“ Angiostatin is a circulating angiogenesis inhibitor and is purified from serum and urine of mice bearing a murine Lewis lung carcinoma. Amino acid sequence analysis reveals that angiostatin is identical to a 38KD internal fragment of mouse plasminogen, consisting of kringle domain 1-4( K1-4 ). It specifically inhibits bFGF induced endothelial cell proliferation, neovascularization in the chick chorioallantoic membrane assay and neovascularization in mouse corneal assay but fails to inhibit proliferation of other cell types, including tumor cells. In the further study, the internal fragment of human plasminogen obtained by digestion with elastase exhibits the same bioactivity as mouse angiostatin. In 1996, O’Reilly and co-workers have shown that angiostatin could inhibit some series of carcinoma growth in vivo, although angiostatin fails to inhibit proliferation of tumor cells. It is also reported that the kringle domain 1-5 of human plasminogen had higher activity of the growth inhibition of T241 fibrosarcoma than angiostatin. Because the half-life of human angiostatin is short and the production of bioactive angiostatin remains to be a difficult task, We tried to use consistently expressed tumor cells of human angiostatin and related fragments and to investigate the efficacy of angiostatin and related proteins inhibition of tumor growth. First, we obtained full length human plasminogen from human liver cDNA pool by PCR and constructed different fragments( K1-5, K1-4 and K1-3+K5 ) in mammalian expression vector( pEGFP-N1 ). Then, the recombinant plasmid was transfected into HEK-293 cells and mouse Lewis lung carcinoma cell line. The stable clones were selected and expression of kringle domains were demonstrated by RT-PCR and dot blotting. The anti-proliferation activities of angiostatin and related proteins secreted in conditioned medium were evaluated. The conditioned medium of the transfected cells can inhibit endothelial cells proliferation but fails to inhibit tumor cell growth. In vivo test, implantation of stable clones expressing human angiostatin and related proteins in C57/Bl6 mice inhibit primary tumor growth by a range from 39% to 77%. Furthermore, we demonstrated that angiostatin had anti-angiogenesis activity by immuno -histochemical analysis of the tumor tissues with anti-CD31 antibody. We therefore set up a system which can be used to study the effect of anti-tumorigenesis by different human angiostatin and related protein fragments, and provide an approach to gene therapy.
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Partzsch, Bernhard. "Identifizierung und Isolierung von Angiostatin aus dem Urin bei Patienten mit Prostatakarzinom." Doctoral thesis, 2004. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-17814.
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Die Angiogenese beschreibt einen entscheidenden Schritt für Tumorwachstum und Metastasierung. Die Tendenz, neue Blutgefäße zu bilden, wird durch das Gleichgewicht angiogener und nicht-angiogener Faktoren bestimmt. In einer Reihe eleganter tierexperimenteller Versuche gelang es O`Reilly erstmals einen tumorassoziierten Inhibitor der Angiogenese, den er Angiostatin nannte, nachzuweisen und zu isolieren. Uns gelang es, im Western-Blot Angiostatin und Angiostatin-Spaltprodukte sowohl aus dem Urin von PCa-Patienten als auch aus dem Urin gesunder Probanden nachzuweisen und zu isolieren. Die anti-angiogene Wirksamkeit des von uns isolierten Proteins wurde im Endothelzellkultur-Assay bestätigt. Eine Differenzierung gesunder Personen von PCa-Patienten war aufgrund der kleinen Fallzahlen nicht möglich. Der Nachweis von Angiostatin bei Gesunden belegt aber, dass anti-angiogene Proteine unabhängig vom Vorhandensein maligner Tumore im Urin ausgeschieden werden. Es bleibt zu vermuten, dass Angiogenese-Inhibitoren ähnlich den Gerinnungsfaktoren bei Bedarf aktiviert und inaktiviert werden können. Der Angiogenese zugrunde liegende Mechanismen und beteiligte Faktoren sind Bestandteil intensiver Forschung. Unklar ist, ob Angiogenese-Inhibitoren in Zukunft in der Krebstherapie die Rolle spielen werden, die man ihnen bei ihrer Entdeckung zuschriebAngiogenesis is an essential component for tumor growth and metastasis. The formation of new blood vessels is controlled by the balance of angiogenic and angiogenesis-inhibiting factors. In several animal experiments O`Reilly was able to isolate a tumorassociated inhibitor of angiogenesis, which was named angiostatin. We ware able to detect angiostatin and angiostatin fragments in the Western blot analysis as well in the urine of patients with prostate cancer as in the urine of healthy persons. The anti-angiogenic function of the isolated protein was confirmed in an endothelial proliferation assay.Because of the small number of cases it was not possible to differentiate between healthy people and patients with prostate cancer. The detection of angiostatin in the urine of healthy persons shows, that antiangiogenic proteins are excreted with the urine even if there is no tumor. It might be possible, that inhibitors of angiogenesis – similar to the factors of the coagulation system – could be activated and inactivated if required. The mechanism of angiogenesis and the included factors are part of an intensive research. It is not clear yet, whether inhibitors of angiogenesis would be that important for therapy of tumors, that they were guessed to be when they were discovered
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盧諭德. "Studies on the structural and functional relation between angiostatin and its related proteins." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/74675602193173585637.
Full textAbstract:
碩士國立成功大學
生物化學研究所
88
Angiogenesis plays an important role in variety of physiological processes such as embryonic development, wound healing, and tissue or organ regeneration. These processes are highly regulated and occur within a short period. Abnormal growth of new blood vessels can lead to the progression of many diseases such as diabetic retinopathy, rheumatoid arthritis and tumor growth. Direct experimental evidence shows that angiogenesis is necessary for tumor growth and metastases. Angiostatin is an endogenous anti-angiogenic agent and initially isolated from urine and sera of mice bearing Lewis lung carcinoma. It was found to inhibit endothelial cell proliferation and to block basic FGF-elicited angiogenesis in corneal micropocket assay. Microsequence analysis of angiostatin revealed that it had greater than 98% identity to an internal fragment of plasminogen which includes the first four kringle domains. Many studies have demonstrated that individual and multiple kringle fragments of angiostatin have different inhibitory activity of angiogenesis. Because each kringle contains the triple loop disulfide-linked structures, we want to understand the relationship between the structure and function of angiostatin and its related fragments. We selected three specific cleavage sites in kringle 4 and kringle 5, ie. 543, 555, 560 in kringle 5 and 454, 449, 437 in kringle 4 to generate various fragments of plasminogen. In addition, we also prepared two wild type fragments, ie. K5567(wt) and K4462(wt). Various fragments were successfully expressed in Pichia Pastoris expression system and purified from the inducing medium by lysine affinity chromatography. In endothelial cell migration assay, we found that the fragments which contained denatured kringle 5 had more potent inhibitory activity than K5wt and K4wt. The same situation happened to the fragments which contained denatured kringle 4, implying that the kringle conformation may shield kringle domain from effectively interacting with endothelial cells.
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López, José Luis. "Estudios sobre el crecimiento de E. Coli recombinante, que expresa angiostatina mediante un sistema inducible por baja concentración de fosfato." Tesis, 2010. http://hdl.handle.net/10915/2200.
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嚴玉婷. "STUDY OF THE FUNCTIONAL DOMAIN OF ANGIOSTATIN AND DEVELOPMENT OF TARGETED THERAPY FOR CANCER." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/23480470925748867955.
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碩士國立臺灣大學
口腔生物科學研究所
91
The treatment of cancer requires the cooperative efforts of widely divergent medical specialties. In the past, radiotherapy and surgical removal of solid tumor mass have been applied for many years. New chemotherapeutic drugs have created important roles in treatment of cancer, but the most important problem is multiple-drug resistance. The genetic instability, heterogeneity, and high mutation rate of malignant cells cause the cancer cells to survive through drug resistance after chemotherapy. Since solid tumor growth and metastasis are dependent on angiogenesis of the tumor, a new approach to overcome multiple-drug resistance is via anti-angiogenesis therapy. Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of tumor angiogenesis and metastasis in mice. Angiostatin can inhibit endothelial cell growth in tumor angiogenesis process, but the functional domain is not documented. In this study, we have isolated angiostatin from human plasma. The molecular weight of the purified angiostatin is between 40-48 kDa. The purified angiostatin exhibited potent inhibitory activity to endothelial cells with an efficiency concentration (EC50) of 4 μM. Furthermore, we have established nine monoclonal antibodies against angiostatin; four functional monoclonal antibodies were further confirmed to inhibit the function of the angiostatin. We also performed phage display analysis to find out the functional domain of angiostatin. Angiostatin and synthetic peptide mimic were demonstrated to inhibit HUVEC proliferation and induce HUVEC apoptosis. For oral cancer targeted therapy, we have examined a chemically synthesized preparation of Liposome-encapsulated Doxorubicin (LD) that was linked to angiostatin or synthetic peptide mimic. We found that the synthetic peptide-LD and angiostatin-LD could reduce tumor growth and decrease side effect in vivo. This approach may provide a new strategy for the rational design of anti-angiogenesis cancer therapies.
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Shih, Yung-Shen, and 施詠紳. "Baculovirus-mediated Long Term Expression of Human Endostatin::Angiostatin Fusion Protein for Cancer Gene Therapy." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/10349041184420275895.
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碩士國立清華大學
化學工程學系
98
Angiogenesis is tightly held together with the further development of solid tumors, and antiangiogenic therapy remains highly exceptional promise as an inhibitor in several cancer-related diseases. In this study, the gene encoding human endostatin and angiostain fusion protein (hEA) was directly delivered to tumor cells by baculoviral vectors combined with Sleeping Beauty (SB) transposon system for long-term inhibition of tumor-induced angiogenesis. We first constructed three recombinant baculoviruses: Bac-hEA/w harboring the hEA gene under the transcriptional control of cytomegalovirus immediate-early (CMV-IE) promoter and the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) inserted into downstream of hEA gene to enhance the expression of therapeutic protein, Bac-SB-T2-hEA/w harboring the same gene expression cassette flanked by inverted repeats (IR) as a whole SB transposon and the expression cassette of SB tansposase (i.e. in cis), and Bac-SB-T2-luc/w with luciferase gene substituting for hEA gene of Bac-SB-T2-hEA/w. In animal studies, baculoviral vectors themselves showed marked anti-tumor effect without reduction of tumor vessel density in early days after virus injection, and long-term expression of hEA demonstrated decrease in tumor-induced angiogenesis (p < 0.05) and consequently retarded the tumor growth more effectively.
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Partzsch, Bernhard [Verfasser]. "Identifizierung und Isolierung von Angiostatin aus dem Urin bei Patienten mit Prostatakarzinom / vorgelegt von Bernhard Partzsch." 2006. http://d-nb.info/979726891/34.
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Liao, Ai-chi, and 廖艾琪. "Cloning of the genes of angiostatin and endostatin : Application of the antiangiogenic factors in cancer gene therapy." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/49249526005492462043.
Full textAbstract:
碩士國立臺灣大學
微生物學研究所
87
Based on the observation that solid tumor growth and metastasis are angiogenesis dependent, antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial target, an absence of drug resistance. To promote tumor regression and to maintain dormancy, anti-angiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. Angiostatin and endostatin , the proteolytic fragments of plasminogen and collagen XVIII, respectively, have recently been shown to potently inhibit endothelial proli-feration in vitro and tumor growth in vivo. As a step toward this goal, we have generated re-combinant retroviral vectors that carry genes coding for human angiostatin(HA), human endo-statin(HE), and mouse endostatin(ME). These retroviral vectors successful-ly transduced angiostatin and endostatin cDNA in two rat tumor cell lines, GP7TB and RT2. We confirmed by Western blotting analysis that the anti-angiogenic factors could be secreted out of the cells. In vitro bioassays indicated that only the tumor cells expressing HA and HE could inhibit HUVE cells proliferation. Nevertheless, all three anti-angiogenic factors exhibited the potentials of regressing tumor in vivo. We also generated recombinant adenoviral vectors which carried genes coding for HA or ME(Ad-HA or Ad-ME). Using the recombinant adenoviruses to infect HUVE cells at an MOI of 300, the proliferation of HUVE cells were inhibited by Ad-ME, but not by Ad-HA. However, we can't negate the biological activity of Ad-HA currently, because the cDNA fragment was obtained from the same source as that in construction of recombinant retroviral vectors. We also constructed the pShuttle-AFP-E1 plasmid which could specifically express E1 protein in hepatoma cell lines. We have confirmed that expression of AFP-E1 could limit the replication of adenoviruses in hepatoma cells. Next step we will generate recombinant adenoviruses containing the AFP-E1 fragment. Our purpose is to construct a conditionally replicative adenovirus in order to improve the effects of adenoviral gene therapy. In conclusion, in this study, we have generated recombinant retroviral and adenoviral vectors carrying antiangiogenic factor cDNAs. These vectors can provide a potential use for tumor gene therapy in combination with immunogene therapy.
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TaShou, Tang, and 唐大綬. "The mechanisms of anticancer drug effects (AHMA-ethyl-carbamate, angiostatin and RGD peptide) on an animal model bearing with nasopharyngeal carcinoma tumor masses." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/19915032686229346904.
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碩士國立臺灣大學
病理學研究所
88
Nasopharyngeal carcinoma (NPC) is one of the most common cancers amoung Chinese living in southern China, Hong-Kong, Singapore and Taiwan. Our laboratory has established nine NPC cell lines from NPC patients. These cell lines have been used to study various topics in the past several years. The treatment of cancer requires the cooperative efforts of widely divergent medical specialities. In the past, the radiotherapy and surgical removal of NPC tumor masses have been applied for years. Now, new chemo-therapeautic drugs have created important roles of treatment in cancer. In this setting the clinical development of a treatment must be based on a thorough understatnding of the potential for beneficial response and of the pharmacologic, pathologic, toxicological, and physiological knowledge. The genetic instability, heterogeneity, and high mutation rate of cancer cells cause the carcinoma to survive after chemotherapy. The cancer cells might activate their multi-drug resistant potential and resulting in difficulty to treat the tumor. A new solution for multi-drug resistance is the way of anti-angiogenesis. Since the vascular endothelial cells belong to normal cells, there’s no problem with the multi-drug resistance. The present experiment included three anti-cancer drugs to treat NPC cells. (1) AHMA-Ethyl-Carbamate (AHMA-EC): This chemical compound was provided by Dr. Su from Academia Sinica, Taipei. We proved that this drug can kill NPC cells in vitro and in vivo. The anti-cancer phenomenon might be caused through more than one pathways. One possible mechanism was as follow: AHMA-EC bound to DNA and topoisomerase Ⅱ, then the complex inhibited transcription of Topo Ⅱ. Finally, AHMA-EC causes apoptosis. The other pathway was to supress hWee 1, a kinase transcript, resulting in blocking cell cycle at G2/M phase, AHMA-EC may also involve other undefined mechanism to tumor cells. We have also set up a positive control experiment with VP-16 (VepesidTM), an anti-cancer chemo -therapeutic compound which also inhibited Topo II enzyme activity. The result showed that VP-16 also inhibited both Topo II and hWee 1 transcription. In contrast to AHMA-EC, the effective dose of VP-16 was larger than AHMA-EC. In conclusion, AHMA—EC can kill and surpress tumor cell proliferation in the animal model experiment. AHMA-EC is less toxic than VP-16. AHMA-EC can be a potential anti-cancer drug in clinical treatment. (2) Angiostatin: We set up an animal model with NPC tumors to study the anti-cancer effect of angiostatin. Our results show that angiostatin can inhibit human umbilical vascular endothelial cells (HUVEC). In animal model experiments, angiostatin did inhibit the growth of NPC tumor masses on SCID mice. These result proved that the theory of anti-cancer with anti-angiogenesis is effective. For developing new way to anti-tumor, anti-angiogenesis will be a good new method to treat tumor mass. (3) P1: This polypeptide is designed containing arginine-glycine-aspartate sequence. P1 could inhibit tumor partially in animal model. We also found that RGD peptide can inhibit HUVEC. In animal model experiments, P1 could inhibit tumor mass partially. We should study more detail about P1 function to identify its mechanism and to find the way to protect the peptide degraded in vivo.
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Shen, Che-piao, and 沈哲標. "EVALUATE THE COMBINED EFFICACY TO ELIMINATE TUMOR OF TWO RECOMBINANT ADENO-ASSOCIATED VIRUSES EXPRESSING HUMAN PAPILLOMA- VIRUS TYPE16 E7 PEPTIDE DNA FUSED WITH HEAT SHOCK PROTEIN 70 DNA AND ANGIOSTATIN GENE." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/21003310035738936023.
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碩士國防醫學院
微生物及免疫學研究所
90
According to the newest report about the major death causes in Taiwan from the Department of Health in 2000 ,the first one is carcinoma ,and cervical cancer is the fourth in carcinoma. human papilloma virus(HPV) type16 and type18 are the main pathogens, their E5,E6,E7gene are also major oncogenes. At pesent,there are many tumor vaccines based on these genes in the world. A tumor vaccine, it must induce cellular immunity especially in cytotoxic T lymphocyte effect to clear the tumor. Our lab had proved that adeno-associated virus expressing E7CTL-hsp DNA(rAAV-E7CTL-hsp) will initiate well immune responses to inhibit the growth of tumor before.on the basis of rAAV-E7CTL-hsp,this report will try to combine another adeno-associated viral vectors expressing angiostatin gene ( rAAV-mAng-HA),to observe the efficacy to eliminate tumor of this combined therapy.this experiment also evaluate the immune response in C57BL/6J mice induced from rAAV-E7CTL-hsp injection by flow cytometry analysis. it indicated that rAAV-E7CTL-hsp indeed can induce E7-specific CTL immune response in mice ,and the same as the result by 51Cr-release CTL assay. On the combined therapy of animal model, the core are induced in situ tumor model and induced metastsis tumor model. results told that if we give mice rAAV-E7CTL-hsp and rAAV-mAng-HA at the same time by intramuscular injection, compared to that with only rAAV-E7CTL-hsp injection, we were not see the enhanced effect to eliminate tumor growth. although results are not the same as which we expect, combined therapy will have synergetic effect, this strategy which combined immunotherapy and antiangiogenesis theories still have it’s potential to develop if we try hard to find out the knack.