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1
Daghriri, Hassan. "Studies on Tumour Active Compounds with Multiple Metal Centres." University of Sydney. Biomedical Sciences, 2004. http://hdl.handle.net/2123/595.
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Four tumour active trinuclear complexes: DH4Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)4NH2)2]Cl4, DH5Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)5NH2)2]Cl4, DH6Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)6NH2)2]Cl4, DH7Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd(NH3)2-( H2N(CH2)7NH2)2]Cl4 and one dinuclear complex DHD: [{trans-PtCl(NH3)2}�-{ H2N(CH2)6NH2}{trans-PdCl(NH3)2]Cl(NO3), have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1 H NMR spectral measurements. For the trinuclear complexes, the synthesis has been carried out using a step-up method branching out from the central palladium unit. A purity of about 95% has been obtained by repeated dissolution and precipitation. The activity against human cancer cell lines including ovary cell lines: A2780, A2780 cisR , A2780 ZD0473R , non small lung cell line: NCI-H640 and melanoma: Me-10538 have been determined based on MMT assay. Cell uptakes, DNA-binding have been determined for ovary cell lines: A2780, A2780 cisR . The nature of interaction with pBR322 plasmid DNA and ssDNA has been studied for trinuclear complexes DH4Cl, DH5Cl, DH6Cl and DH7Cl and the dinuclear complex DHD. Interaction of DH6Cl with adenine and guanine has also been studied by HPLC. The compounds are found to exhibit significant anticancer activity against cancer cell lines especially ovarian cancer cell lines: A2780, A2780 cisR and A2780 ZD0473R . DH6Cl in which the linking diamine has six carbon atoms is found to be the most active compound. As the number of carbon atoms in thelinking diamine is changed from the optimum value of six, the activity is found to decrease, illustrating the structure-activity relationship. The increase in uptake of the trinuclear complexes in A2780 cell line with the increase in size of the linking diamine coupled with the low molar conductivity values found for the solutions of the compounds suggest that the compounds would remain in solution as undissociated �molecules� and hence could cross the cell membrane by passive diffusion. Much lower resistance factors for the all the multinuclear compounds including DHD as applied to A2780 cisR cell line, as compared to that for cisplatin, suggest that the compounds are able to overcome multiple mechanisms of resistance operating in the cell line. All of the multinuclear complexes are expected to form long-range interstrand GG adducts with DNA, causing irreversible global changes in the DNA conformation but unlike cisplatin do not cause sufficient DNA bending to be recognized by HMG 1 protein. Increasing prevention of BamH1 digestion with the increase in concentration of the multinuclear compounds also provide support to the idea that the compounds because of the formation of a plethora of interstrand GG adducts are able to cause irreversible changes in DNA conformation. The results of the study show that indeed new trinuclear tumour active compounds can be found by replacing the central platinum unit in BBR3464 with other suitable metal units.
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Daghriri, Hassan. "Studies on Tumour Active Compounds with Multiple Metal Centres." Thesis, The University of Sydney, 2003. http://hdl.handle.net/2123/595.
Full textAbstract:
Four tumour active trinuclear complexes: DH4Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)4NH2)2]Cl4, DH5Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)5NH2)2]Cl4, DH6Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd( NH3)2(H2N(CH2)6NH2)2]Cl4, DH7Cl: [{trans-PtCl(NH3)2}2m-{trans-Pd(NH3)2-( H2N(CH2)7NH2)2]Cl4 and one dinuclear complex DHD: [{trans-PtCl(NH3)2}�-{ H2N(CH2)6NH2}{trans-PdCl(NH3)2]Cl(NO3), have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1 H NMR spectral measurements. For the trinuclear complexes, the synthesis has been carried out using a step-up method branching out from the central palladium unit. A purity of about 95% has been obtained by repeated dissolution and precipitation. The activity against human cancer cell lines including ovary cell lines: A2780, A2780 cisR , A2780 ZD0473R , non small lung cell line: NCI-H640 and melanoma: Me-10538 have been determined based on MMT assay. Cell uptakes, DNA-binding have been determined for ovary cell lines: A2780, A2780 cisR . The nature of interaction with pBR322 plasmid DNA and ssDNA has been studied for trinuclear complexes DH4Cl, DH5Cl, DH6Cl and DH7Cl and the dinuclear complex DHD. Interaction of DH6Cl with adenine and guanine has also been studied by HPLC. The compounds are found to exhibit significant anticancer activity against cancer cell lines especially ovarian cancer cell lines: A2780, A2780 cisR and A2780 ZD0473R . DH6Cl in which the linking diamine has six carbon atoms is found to be the most active compound. As the number of carbon atoms in thelinking diamine is changed from the optimum value of six, the activity is found to decrease, illustrating the structure-activity relationship. The increase in uptake of the trinuclear complexes in A2780 cell line with the increase in size of the linking diamine coupled with the low molar conductivity values found for the solutions of the compounds suggest that the compounds would remain in solution as undissociated �molecules� and hence could cross the cell membrane by passive diffusion. Much lower resistance factors for the all the multinuclear compounds including DHD as applied to A2780 cisR cell line, as compared to that for cisplatin, suggest that the compounds are able to overcome multiple mechanisms of resistance operating in the cell line. All of the multinuclear complexes are expected to form long-range interstrand GG adducts with DNA, causing irreversible global changes in the DNA conformation but unlike cisplatin do not cause sufficient DNA bending to be recognized by HMG 1 protein. Increasing prevention of BamH1 digestion with the increase in concentration of the multinuclear compounds also provide support to the idea that the compounds because of the formation of a plethora of interstrand GG adducts are able to cause irreversible changes in DNA conformation. The results of the study show that indeed new trinuclear tumour active compounds can be found by replacing the central platinum unit in BBR3464 with other suitable metal units.
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Tayyem, Hasan. "Studies on new tumour active compounds with one or more metal centres." zConnect to full text, 2006. http://hdl.handle.net/2123/1727.
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Thesis (Ph. D.)--University of Sydney, 2007.<br>Title from title screen (viewed may 17, 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Biomedical Sciences, Faculty of Health Sciences. Degree awarded 2007; thesis submitted 2006. Includes bibliographical references. Also issued in print.
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Tayyem, Hasan Mohammad. "Studies on new tumour active compounds with one or more metal centres." Thesis, The University of Sydney, 2006. http://hdl.handle.net/2123/1727.
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The present study deals with the synthesis, characterization, determination of anticancer activity of three mononuclear trans-planaraminepalladium(II) complexes code named TH5, TH6 and TH7 and three trinuclear complexes code named TH1, TH8 and TH14. The activity of the compounds against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, DNA-binding and nature of interaction with pBR322 plasmid DNA have been determined. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH5, TH6, TH7, TH1 and TH8 bind with DNA forming mainly interstrand GG adducts that causes more of a global change in DNA conformation. Although TH5, TH6 and TH7 each have two substituted pyridine ligands in a trans-geometry (3-hydroxypyridine in TH5, 2-hydroxypyridine in TH6 and 4-hydroxypyridine in TH7), the compounds differ in their activity against ovarian cancer cell lines, indicating that non-covalent interactions involving the hydroxyl group may be playing a significant role in activity of the compounds. Among trinuclear complexes TH1 is found to be significantly more active than cisplatin. It is actually twice as active as cisplatin against the parent cell line A2780, thirteen times as active as cisplatin against the cisplatin-resistant cell line A2780cisR and 11.5 times as active as cisplatin against the cell line A2780ZD0473R. Whereas the resistance factor for cisplatin as applied to the cell lines A2780 and A2780cisR cell lines is 12.9 that for TH1 is 1.98. The results suggest that TH1 has been able to significantly overcome resistance operating in A2780cisR cell line. The compound is soluble in water so that it may be taken orally. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin. Although platinum drugs use a shot-gun approach to kill cancerous cells, widespread use in the clinic and increasing volume of their sale indicate that even in the genomic age, there is still need for shot-gun drugs in the clinic.
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Tayyem, Hasan Mohammad. "Studies on new tumour active compounds with one or more metal centres." Faculty of Health Sciences, 2006. http://hdl.handle.net/2123/1727.
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Doctor of Philosophy(PhD)<br>The present study deals with the synthesis, characterization, determination of anticancer activity of three mononuclear trans-planaraminepalladium(II) complexes code named TH5, TH6 and TH7 and three trinuclear complexes code named TH1, TH8 and TH14. The activity of the compounds against human cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, DNA-binding and nature of interaction with pBR322 plasmid DNA have been determined. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH5, TH6, TH7, TH1 and TH8 bind with DNA forming mainly interstrand GG adducts that causes more of a global change in DNA conformation. Although TH5, TH6 and TH7 each have two substituted pyridine ligands in a trans-geometry (3-hydroxypyridine in TH5, 2-hydroxypyridine in TH6 and 4-hydroxypyridine in TH7), the compounds differ in their activity against ovarian cancer cell lines, indicating that non-covalent interactions involving the hydroxyl group may be playing a significant role in activity of the compounds. Among trinuclear complexes TH1 is found to be significantly more active than cisplatin. It is actually twice as active as cisplatin against the parent cell line A2780, thirteen times as active as cisplatin against the cisplatin-resistant cell line A2780cisR and 11.5 times as active as cisplatin against the cell line A2780ZD0473R. Whereas the resistance factor for cisplatin as applied to the cell lines A2780 and A2780cisR cell lines is 12.9 that for TH1 is 1.98. The results suggest that TH1 has been able to significantly overcome resistance operating in A2780cisR cell line. The compound is soluble in water so that it may be taken orally. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin. Although platinum drugs use a shot-gun approach to kill cancerous cells, widespread use in the clinic and increasing volume of their sale indicate that even in the genomic age, there is still need for shot-gun drugs in the clinic.
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Subbotina, Beztsinna Nataliia. "Riboflavin-based amphiphiles for tumour-targeted nanosystems." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0254/document.
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La riboflavine (RF) est une vitamine essentielle pour la croissance et le développement cellulaire. Elle possède des propriétés physico-chimiques intéressantes et est internalisée dans les cellules par des transporteurs spécifiques. Le premier objectif de ce projet était de synthétiser des dérivés amphiphiles de la RF (RFA) et d'étudier leurs capacités d'auto-assemblages. Le second objectif était d'insérer les RFA dans des liposomes et d'évaluer leur efficacité de ciblage tumoral in vitro et in vivo. La préparation des différents RFA repose sur l'ajout d'un lipide en différentes positions de la RF. L’un d'eux, de type phospholipide (RfdiC14) a été capable de former des objets tridimensionnels de taille μm constitués de lamelles multicouches dont l’architecture et la dynamique sont très différentes de celles des phospholipides classiques. L’insertion de RfdiC14 dans des liposomes est efficace et n’influence pas leurs propriétés physico-chimiques. Les liposomes fonctionnalisés ont montré une internalisation cellulaire spécifique dans les lignées A431, PC3 et HUVECs. Afin de tester l’efficacité du ciblage tumoral in vivo, un analogue de RfdiC14 portant un espaceur PEG a été préparé puis inséré dans des liposomes péguylés. Grâce à un marquage adéquat (ICG et DiR), leur accumulation tumorale a été suivie par imagerie photoacoustique dans un modèle A431 et leur biodistribution évaluée par imagerie μCT/FMT dans un modèle PC3. Les résultats montrent une légère amélioration de l’accumulation tumorale dans les xénogreffes A431 et une augmentation du ciblage vasculaire dans le modèle tumoral PC3. La biodistribution globale des liposomes marqués est comparable à celle des contrôles<br>Riboflavin (RF) is an essential vitamin for cell growth and development. It possesses interesting physicochemical properties and is internalized by the cells through specific transporters. The first aim of this study was to prepare amphiphile derivatives of RF (RFA) and study their auto-assembly. The second aim was to insert RFA into established drug delivery systems and test their tumour-targeting potential in vitro and in vivo. RFA were prepared by the molecule functionalization with lipid moieties in different positions. One of them, a phospholipid-like derivative (RfdiC14) was able to self-assembly in aqueous solutions into μm-sized 3D objects constituted from slightly curved multilayer lamellas. The bilayer architecture and dynamics were very different from ordinary phospholipids. In contrast, the insertion of small amount of RfdiC14 in a liposome did not influence membrane dynamics and physicochemical characteristics. RfdiC14-functionalised liposomes displayed high and specific uptake in vitro in A431, PC3 cells and HUVECs. The efficiency of RF targeting was also tested in vivo. For that purpose, liposome composition was optimized and a new RF amphiphile with a PEG spacer between RF and lipid was prepared. The tumour accumulation of the liposomes labelled with ICG was studied by photoacoustic imaging in A431 tumour model. The biodistribution of DiR labelled liposomes was accessed by combined μCT/FMT imaging in PC3 tumour model. The results show slight improvement of the tumour accumulation in A431 xenographts and the enhancement of vascular targeting in PC3 tumour model. The overall biodistribution of the RF-targeted liposomes was comparable to control
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Lavaud, Mélanie. "Identification des acteurs clés impliqués dans le développement du tissu osseux et l'évolution des ostéosarcomes par études des super-enhancers actifs." Thesis, Nantes Université, 2022. http://www.theses.fr/2022NANU1019.
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Les super-enhancers (SE) correspondent à des groupement d'enhancers qui recrutent le complexe transcriptionnel pour induire la transcription de leurs gènes cibles plus efficacement que les enhancers. Ils régulent des gènes clés définissant l'identité cellulaire dans des conditions physiologiques et pathologiques. Les objectifs de ce projet de thèse étaient de caractériser le développement osseux normal par l'étude des gènes clés de l'ostéoblastogenèse et de l'ostéoclastogenèse et de caractériser l'évolution métastatique de l'ostéosarcome (OS), la tumeur osseuse primitive maligne la plus fréquente. Nous avons traqué la reprogrammation épigénétique qui se produit au cours de l'ostéoclastogenèse, et associé les SEs actifs dynamiques à leurs gènes cibles potentiels. Ainsi, nous avons pu observer un profil dynamique d'enhancers actifs qui stimule la transcription de gènes clés définissant l'identité des ostéoclastes. L'expression de ces gènes semble être particulièrement affectée par l'exposition au diuron, pesticide suspecté de provoquer des troubles du développement squelettique, altérant la maturation des ostéoclastes. Afin d'identifier les facteurs de transcription (TFs) impliqués dans l'ostéoblastogenèse, nous avons traqué les gènes codant pour des TFs induits par des SEs actifs spécifiques de l'état de différenciation dans un modèle in vitro de différenciation ostéoblastique de cellules souches mésenchymateuses (CSMs). Un ChIP-Sequencing contre la marque H3K27ac des enhancers actifs a été réalisé sur des cellules traitées et non traitées avec du milieu de différenciation à différents temps, ainsi qu'un RNA-Sequencing aux mêmes temps. Nous avons identifié 3 TFs, clés pour l'ostéoblastogenèse, comme cibles de SEs actifs spécifiques du stade de différenciation tardif et un TF induit par un SE spécifique aux CSMs. Les modifications de l'expression de ces TFs liées aux SEs peuvent être des stratégies prometteuses pour lutter contre divers troubles du tissu osseux. En parallèle, nous avons comparé les profils des SEs actifs dans différentes lignées cellulaires d’OS et dans des échantillons tumoraux extraits de sites primaires et métastatiques. Le regroupement hiérarchique des profils de SEs actifs nous a permis de distinguer deux ensembles d'échantillons d’OS : un groupe contenant les échantillons primaires et la lignée cellulaire MG63 et un second groupe contenant les échantillons métastatiques et les lignées cellulaires U2OS et HOS-MNNG. Nous avons identifié 3 gènes qui sont induits par des SEs actifs spécifiques aux métastases. Les sous expressions simultanées des 3 gènes identifiés diminuent les capacités d'infiltration et de motilité des HOS-MNNG et donc leur capacité métastatique. Le suivi des gènes cibles des profils évolutifs des SEs actifs pourrait par conséquent être utilisé pour l'identification des gènes qui gouvernent la différenciation cellulaire et façonnent le comportement cellulaire, qu'il soit physiologique ou pathologique<br>Super-enhancers (SEs) are cluster of enhancers that recruit the transcriptional complex to induce the transcription of their target genes more efficiently than enhancers. They regulate key cell identity defining genes in physiological and pathological conditions. The objectives of this thesis project were to characterize normal bone development through the study of osteoblastogenesis and osteoclastogenesis driver genes and to characterize the metastatic evolution of osteosarcoma (OS), the most frequent malignant primary bone tumour. We tracked the epigenetic reprogramming occurring during osteoclastogenesis, and associated dynamic active SEs to their potential target genes. As such, we were able to observe a dynamic active enhancers profile that boosts transcription of key osteoclasts identity defining genes. The expression of these genes seemed to be particularly affected by diuron exposure, pesticide suspected to cause skeletal disorders, impairing osteoclasts maturation. In order to identify transcription factors (TFs) involved in osteoblastogenesis, we tracked TF-encoding genes induced by differentiation state specific active SEs in an in vitro model of mesenchymal stem cells (MSCs) osteoblastic differentiation. ChIP-Sequencing for the active enhancers marker H3K27ac was performed in differentiation medium treated and untreated cells at different time points along with RNA-Sequencing at the same time points. We identified 3 TFs, key for osteoblastogenesis, as targets of late stage differentiation specific active SEs and one MSCs specific SE induced TF. Expression modifications of these SEs related TFs may be promising strategies to fight against various bone disorders. In parallel, we compared the active SEs profiles in different OS cell lines and tumor samples extracted from primary and metastatic sites. Hierarchical clustering on the active SEs profiles allowed us to distinguish two sets of OS samples: one group containing the primary samples and MG63 cell line and the other containing metastatic samples with U2OS et HOS-MNNG cell lines. We identified 3 genes that are induced by metastasis specific active SEs. Simultaneous down expressions of the 3 identified genes decrease HOS-MNNG infiltration and motility capacities and thus their metastatic capacity. Tracking target genes of the evolving active SEs profiles could as a result be used for the identification of genes that drive cell differentiation and shape cellular behavior, whether physiological or pathological
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Milbank, Edward. "Extracellular vesicles as a therapeutic strategy to prevent or reverse obesity and its metabolic complications in the field of nanomedicine Extracellular vesicles: Pharmacological modulators of the peripheral and central signals governing obesity Microparticles from apoptotic RAW 264.7 macrophage cells carry tumour necrosis factor-a functionally active on cardiomyocytes from adult mice." Thesis, Angers, 2016. http://www.theses.fr/2016ANGE0074.
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A ce jour, les thérapies anti-obésité restent limitées. De récente études ont fourni des résultats prometteurs en démontrant une diminution du poids de la souris via une injection stéréotaxique d’une forme dominante négative de l’AMPK (AMPK DN) directement dans le noyau ventromédial hypothalamique (VMH). Cependant, le potentiel thérapeutique de cette thérapie génique se voit entravé par une libération non spécifique de l’AMPK suite à une injection intraveineuse, plus adaptée à une approche clinique. Nous avons donc développé une approche de « nanobiomédecine » en utilisant des exosomes - nanovésicules contenant des lipides, des protéines et des acides nucléiques - pour délivrer l’AMPK DN spécifiquement au niveau du VMH. Des cellules dendritiques immatures ont été utilisées pour produire des exosomes non-inflammatoires. Pour permettre le ciblage spécifique du VMH par les exosomes, les cellules dendritiques ont été transfectées pour exprimer Lamp2b, une protéine exosomale, fusionnée au peptide de ciblage neuronal RVG. De façon intéressante, les exosomes Lamp2b-RVG ont été localisés au niveau du cerveau suite à une injection intraveineuse. Les exosomes Lamp2b-RVG ont ensuite été chargés par l’AMPK DN sous le contrôle d’un promoteur spécifique du VMH, apportant une double spéficité tissulaire aux exosomes. Les exosomes Lamp2b-RVG chargés avec l’AMPK DN induisaient une diminution de la phosphorylation de l’acetyl-CoA carboxylase dans des cellules Neu2A in vitro. De plus, l’injection intraveineuse d’exosomes Lamp2b-RVG chargés avec l’AMPK DN induisait une perte de poids de l’animal après 6 jours de traitement, démontrant le potentiel de cette approche de « nanobiomédecine »<br>Actual pharmacological therapies for treating obesity are limited. Promising results on decreasing mice body weight were obtained using a ventromedial nucleus hypothalamic (VMH) stereotaxic injection of a dominant negative isoform of AMPK (AMPK DN). However, DNA-mediated therapeutic potential is hampered by inadequate tissue specific delivery following a systemic injection - more adapted to a bedside approach -. Herein, we developed a nanobiomedicine approach using exosomes - nano-scaled endogenous vesicles containing lipids, proteins and nucleic acids - to deliver DNA in a hypothalamic specific way. Immature dendritic cells were used to generate non inflammatory exosomes. Exosome neuronal targeting aptitudes were achieved by constraining the dendritic cells to express Lamp2b, an exosomal protein, fused to the neuron-specific RVG peptide. Interestingly, DID-labelled Lamp2b-RVG exosomes were found into the mice brain following an intravenous injection. Isolated Lamp2b-RVG exosomes were then loaded by transfection-mediated techniques with AMPK DN under the control of a VMH specific promoter conferring double tissue expression specificity to the exosomes. AMPK DN-loaded exosomes induced a decrease of acetyl-CoA carboxylase phosphorylation in Neu2a neuronal cells in vitro. Furthermore, intravenously injected AMPK DN loaded exosomes induced a decrease of mice body weight following 6 days of treatment, demonstrating the potential of this nanobiomedicine approach
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Barbara, Jeffrey A. J. "The mechanism of action of tumour necrosis factor-[alpha] /." Title page, contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09PH/09phb229.pdf.
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Roelofs, Anke. "Anti-tumour mechanisms of action bisphosphonates and bisphosphonate analogues." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436994.
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Morrow, Dympna Mary Paula. "Tumour promotion : mechanisms of action and modes of prevention." Thesis, University of Ulster, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322414.
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Ruddock, Mark William. "The mechanism of action of the selective tumour radiosensitizer nicotinamide." Thesis, University of Ulster, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287132.
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Sampson, Louise E. "Investigations into the mechanism of action of tumour necrosis factor." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304660.
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Hickman, J. A. "Studies of the mechanism of action of anti-tumour compounds." Thesis, Aston University, 1989. http://publications.aston.ac.uk/21707/.
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Sanders, Paul Michael. "Mechanism of action of a tumour derived lipid mobilising factor." Thesis, Aston University, 2003. http://publications.aston.ac.uk/11005/.
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Cancer cachexia comprises unintentional and debilitating weight loss associated with certain tumour types. Fat loss in cachexia is mediated by a 43kDa Lipid Mobilising Factor (LMF) sharing homology with endogenous Zinc-a2-Glycoprotein (ZAG). LMF and ZAG induced significant lipolysis in isolated epidydimal adipose tissue. This is attenuated by co-incubation with 10mM of antagonist SR59230A and partially attenuated by 25mM PD098059 (indicating b3-AR and MAPK involvement respectively). LMF/ZAG induced in vitro lipid depletion in differentiated 3T3-L1 adipocytes that seen to comprise a significant increase in lipolysis (p<0.01), with only a modest decrease in lipid synthesis (p=0.09). ZAG significantly increased in vitro protein synthesis (p<0.01) in C2C12 myotubes (without an effect on protein degradation). This increase was activated at transcription and attenuated by co-incubation with 10mM SR59230A. Proteolytic digestion of ZAG and LMF followed by sephadex G50 chromatography yielded active fragments of 6-15kDa, indication the entire molecule was not required for bioactivity. Cachexigenic MAC16 cells demonstrated significant in vitro ZAG expression over non-cachexigenic MAC13 (p<0.001). WAT and BAT excised from MAC16 mice of varying weight loss demonstrated increased ZAG expression compared to controls. Dosing of NMRI mice with s/c ZAG failed to reproduce this up-regulation, thus another cachectic factor is responsible. 0.58nM LMF conferred significant protection against hydrogen peroxide, paraquat and bleomycin-induced oxidative stress in the non-cachexigenic MAC13 cell line. This protection was attenuated by 10mM SR59230A indicating a b3-AR mediated effect. In addition, 0.58nM LMF significantly up regulated UCP2 expression (p<0.001), (a mitochondrial protein implicated in the detoxification of ROS) implying this to be the mechanism by which survival was achieved. In vitro, LMF caused significant up-regulation of UCP1 in BAT and UCP2 and 3 in C2C12 myotubes. This increase in uncoupling protein expression further potentiates the negative energy balance and wasting observed in cachexia.
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Darragh, Molly Rose. "Targeting the active serine protease MT-SP1 for tumor detection in vivo." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3398875.
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Griffiths, Stephen Douglas. "The mechanism of action of interferon-#alpha# in hairy-cell leukaemia." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257124.
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Chauchet, Xavier. "Développement d'un vecteur bactérien pour l'immunothérapie anti-tumorale active et spécifique et caractérisation de la réponse immune induite." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENS024/document.
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Malgré les programmes de dépistage mis en place et le vaste arsenal thérapeutique disponible, 8,2 millions de décès dans le monde ont été attribués au cancer pour l'année 2012 (données Globocan 2012, OMS). L'immunothérapie antitumorale est en plein essor et consiste notamment à exploiter le système immunitaire de l'hôte pour obtenir une réponse contre la tumeur. L'utilisation de vecteurs bactériens, capables de délivrer un message antigénique et de stimuler de manière concomittante l'immunité innée, fait partie des approches de vaccination antitumorale prometteuses. Parmi ces vecteurs, une bactérie Pseudomonas aeruginosa mise au point par notre laboratoire présente l'intérêt de pouvoir injecter in vivo des antigènes de tumeur, via son système de sécrétion de type III (SST3), directement dans le compartiment intracellulaire des cellules présentatrices d'antigènes. La voie de présentation du CMH I est ainsi favorisée et permet la génération d'une réponse des lymphocytes T cytotoxiques vis-à-vis de la tumeur exprimant l'antigène. Cependant, la poursuite des études précliniques et cliniques paraît délicate, en raison du risque infectieux lié à une bactérie pathogène, quand bien même atténuée. Lors de ce travail, nous avons donc développé une nouvelle souche de P. aeruginosa Killed But Metabolically Active (KBMA), incapable de se répliquer, mais toujours apte à jouer son rôle de vecteur. Une analyse de la réponse immune antitumorale, suite à l'immunisation par différents vecteurs, a permis de mettre en évidence une forte infiltration de la tumeur par des lymphocytes T CD8+ spécifiques de l'antigène, mais également une protection à long terme liée à la présence d'un pool majoritaire de lymphocytes T CD8+ spécifiques effecteurs mémoires. Enfin nous avons cherché à appliquer cette technologie à l'antigène de tumeur anhydrase carbonique 9 (AC9), exprimé par de nombreuses tumeurs solides chez l'homme<br>Despite cancer screening programs and the available therapeutic armamentarium, 8.2 million deaths worldwide were due to cancer in 2012 (data Globocan 2012, WHO). The antitumor immunotherapy is booming and aims at using the immune system of the host as a response against the tumor. The use of bacterial vectors, able to deliver an antigenic message and concomitantly stimulate innate immunity, is one of the most promising approaches to antitumor vaccination. Among these vectors, the bacterium Pseudomonas aeruginosa developed by our laboratory has the advantage of being able to inject in vivo tumor antigens via its type III secretion system (T3SS) directly in the intracellular compartment of antigen-presenting cells. The MHC I presentation pathway is thus favored and allows the generation of a cytotoxic T lymphocytes response against antigen-expressing tumors. However, further preclinical and clinical studies remain difficult, because of the risk of infection related to a bacterial pathogen, even if attenuated. In this work, we have developed a new strain of P. aeruginosa Killed But Metabolically Active (KBMA) unable to replicate, but still able to play its role as a vector. An analysis of the antitumor immune response following immunization with different vectors, allowed to demonstrate a strong tumor infiltration by antigen-specific CD8+ T lymphocytes, but also a long-term protection related to the presence of a major pool of antigen-specific effector memory CD8+ T cells. Finally we are seeking to apply this technology to the tumor antigen carbonic anhydrase 9 (CA9), expressed by many solid tumors in humans
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Dupouy-Camet, Anne. "Molécules promotrices de la mélanogénèse." Paris 5, 1989. http://www.theses.fr/1989PA05P211.
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Lynch, Eileen Marie. "The effect of oxygen tension on the cytotoxic action of tumour necrosis factor-alpha." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362843.
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Komaragiri, Shravan Kumar. "Mechanism of action of ID4 as a tumor suppressor." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2016. http://digitalcommons.auctr.edu/dissertations/3335.
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Initial studies demonstrated that Inhibitor of DNA binding/differentiation protein 4 (Id4) acts as a tumor suppressor in prostate cancer (PCa). To further confirm and investigate the mechanism by which ID4 acts as a tumor suppressor, herein we concentrated on two different approaches. In the first approach we investigated ID4 role as a tumor suppressor by regulating AKT/PI3K pathway. In the second approach, we examined the role ofld4 in blocking the tumorogenic properties of metastatic PC3 cells. Phosphoinositide 3-kinase/Protein kinase B (PB/AKT) pathway regulates multiple biological processes leading to cell survival, proliferation and growth in cancerous cells. We performed immunohistochemistry (IHC) to determine AKT, pAKT and PTEN protein expression in Id4 knockout mouse prostates and PCa cell lines. IHC on Id4 knockout mouse prostates demonstrated a significant decrease in PTEN expression as compared to normal mouse prostates. Consistent with decrease PTEN, the expression of pAKT expression increased. Similar pattern was observed in PCa cell lines: DU145 cells lacking Id4 had low PTEN as compared to ld4 over-expressing DU 145 cells. In addition, Chromatin immunoprecipitation (Ch!P) analysis also demonstrated an increase in the binding of acetylated p53 on PTEN promoter in the presence of Id4. The second approach demonstrated the tumor suppressor function of Id4 in highly tumorogenic and metastatic PC3 cell line. Interestingly, this study demonstrated that overexpression of Id4 in PC3 cells results in decreased tumorogenecity in part through increased expression of Androgen receptor (AR) and its target genes Cyclin dependent inhibitor I (p21) and FK506-binding protein 51 (FKBPS l ). Apoptosis, migration and cell proliferation decreased in the Id4 overexpressed PC3 cells. Mice injected with PC3 + Id4 cells showed decreased tumor size and volume. IHC studies on tumor xenografts demonstrated increased levels of AR, Ki67, and p21 in Id4 overexpressed xenograft. Collectively, our data indicate that 1D4 acts as tumor suppressor by regulating the levels of PTEN by prompting the binding ofacetylated p53 onto PTEN promoter which eventually results in inhibiting P13K/AKT pathway. Furthermore, Id4 not only increases the expression of AR in PC3 cells but also regulates the factors responsible for AR tumor suppressor activity.
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McHardy, Lianne M. "A study of the mechanism of action of novel inhibitors of tumour cell invasion." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/252.
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Metastasis is the leading cause of death in cancer patients. Tumour invasion and migration are critical aspects of metastatic progression. A forward chemical genetics project was initiated in an effort to identify novel compounds that inhibit tumour invasion. After screening a natural extract library, two novel inhibitors were identified: motuporamine C (MotC) and strongylophorine-26 (STP-26). Structure-activity studies identified dihdyromotuporamine C (dhMotC) as a potent and easily synthesized analogue. In this work, the mechanism of activity of dhMotC and STP-26 was investigated. It was found that both dhMotC and STP-26 affect cellular shape. dhMotC induced thick central actin stress fibres and large focal adhesions and caused cells to contract. STP-26 also induced adhesion formation but it reduced stress fibres and caused increased cell spreading. Both inhibitors activated Rho GTPase, a result which was shown to mediate, in large part, the anti-invasion activity of these molecules. Motuporamines also induce the formation of membrane-rich inclusions at the peri-nuclear region in cells. Motuporamines cause an increase in lysosomal pH and inhibit lysosomal function, such that EGFR/EGF complexes internalized in the presence of dhMotC do not get degradad. This inhibition of EGF degradation is not dependent on Rho activity. However, the anti-invasive activity of motuporamine analogues correlates well with their ability to induce the formation of membrane-rich inclusions. Thus, alteration in membrane trafficking or degradation of cellular membranes may be mechanistically related to the anti-invasion effect of motuporamines. A systematic genome-wide yeast haploinsufficiency screen was employed in an effort to identify possible targets of dhMotC. Yeast screening resulted in a list of 21 mutant strains which showed increased drug sensitivity. Sphingolipid biosynthesis was identified as a target in yeast cells. By testing other genes from the list, ARF1 was identified as a target that partially mediates the anti-invasive activity in human cells. The results of this body of work show that Rho and ARF1 are important molecular players in the mechanism of tumour cell invasion. This knowledge will contribute to the development of future anti-metastasis therapies and to the development of small molecules for use as biological probes to investigate the molecular basis of metastasis.
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Xia, Chang. "The role of reactive oxygen species and PI3K/AKT signaling in tumor angiogenesis." Morgantown, W. Va. : [West Virginia University Libraries], 2006. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=4714.
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Thesis (Ph. D.)--West Virginia University, 2006.<br>Title from document title page. Document formatted into pages; contains xi, 261 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.
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Walker, C. D. "Action of inositol 1,3,4,5 tetrakisphosphate on Ca 2+ movements in L1210 cells." Thesis, University of East Anglia, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368190.
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Burniat, Agnès. "Etude de la tumorigenèse thyroïdienne et des effets anti-prolifératifs de la vitamine D active dans plusieurs modèles murins." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209664.
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Le but de la première partie de ce travail était de mieux comprendre la tumorigenèse thyroïdienne à<p>partir de modèles murins transgéniques développant des tumeurs de la thyroïde. Nous avons ainsi<p>analysé par microarrays l’expression génique au sein de thyroïdes de souris Tg-RP3 exprimant le<p>réarrangement RET/PTC3, responsable de cancers papillaires de la thyroïde chez l’homme (PTC), et<p>de souris Tg-E7 exprimant l’oncogène E7, responsable de cancers du col de l’utérus chez la femme.<p>Ces deux gènes étaient exprimés exclusivement dans la thyroïde grâce à un promoteur thyroglobuline.<p>Nous avons comparé les profils d’expression entre les différents génotypes (sauvages, Tg-RP3 et Tg-<p>E7) mais également entre différents âges (2, 6 et 10 mois). Sur le plan histologique, les souris Tg-E7<p>développaient d’énormes goitres avec une dysplasie de plus en plus marquée, mais n’ont pas démontré<p>de réelles lésions de carcinomes aux différents âges étudiés. Les thyroïdes de souris Tg-RP3<p>démontraient quand à elle une prolifération cellulaire et une croissance plus modérées, mais des<p>remaniements tissulaires plus importants, présents dès 2 mois, avec apparition de lésions de carcinome<p>chez de nombreux animaux essentiellement à 6 et 10 mois. Les résultats de l’analyse de l’expression<p>génique par microarrays rejoignaient ces observations histologiques. Dans les thyroïdes E7, ce sont<p>essentiellement les gènes impliqués dans le cycle cellulaire qui ont démontré une surexpression<p>significative. Dans les thyroïdes RP3, les processus cellulaires les mieux représentés par les gènes<p>surexprimés étaient déjà décrits comme des processus ayant un rôle important dans la tumorigenèse<p>thyroïdienne humaine :l’inflammation, le remodelage du milieu extracellulaire et l’angiogenèse. De<p>plus, plusieurs gènes classiquement surexprimés dans les PTC humains, l’étaient également dans les<p>thyroïdes RP3. Parmi ceux-ci le récepteur de la vitamine D (VDR) et la 1-alpha-hydroxylase<p>(CYP27B1), responsable de la conversion de la 25-hydroxyvitamine D3 en 1,25-dihydroxyvitamine<p>D3, ont particulièrement retenu notre attention étant donné une littérature croissante sur les effets antiprolifératifs<p>et immuno-modulateurs de la 1,25-dihydroxyvitamine D3 (calcitriol). Nous avons donc<p>étudié dans la deuxième partie de notre travail les effets anti-prolifératifs et transcripionnels du<p>calitriol sur plusieurs modèles thyroïdiens in vitro et in vivo. Si nous n’avons pu démontrer d’effets<p>concluants sur des lignées de cancers thyroïdiens humains, nous avons par contre démontré un effet<p>anti-prolifératif, le plus souvent dose-réponse, du calcitriol sur des cultures primaires de thyroïdes de<p>souris sauvages, Tg-RP3, Tg-E7 et humaines. Seule la 24-hydroxylase, intervenant dans l’inactivation<p>de la vitamine D, et le récepteur à la TSH ont démontré une surexpression significative en présence de<p>calcitriol par RTQ-PCR. Une étude d’expression génique par microarrays sur des cultures primaires de<p>thyroïdes RP3 et humaines traitées par éthanol (contrôle) ou calcitriol a permis de mettre en évidence<p>3 gènes significativement régulés dans le même sens, en l’occurrence sous-exprimés, en présence de<p>calcitriol :la nébulette, la thymopoïétine et la cycline E2. Le rôle exact joué par ces trois protéines<p>dans l’effet anti-prolifératif observé reste à déterminer. Les études in vivo de carence alimentaire en<p>vitamine D de souris Tg-RP3 n’ont pas démontré de différences significatives entre le groupe carencé<p>et non carencé que ce soit en termes de croissance glandulaire ou d’expression génique, après 2 ou 6<p>mois de carence. Seule la 1-alpha-hydroxylase est apparue significativement surexprimée après 2<p>mois, surexpression disparaissant après 6 mois. Cette régulation pourrait témoigner d’un mécanisme<p>d’adaptation de la thyroïde qui tente de contrer la carence en vitamine D circulante en augmentant la<p>concentration locale de vitamine D active. Ce phénomène disparaissant à 6 mois, il serait intéressant<p>de prolonger la carence au-delà de 6 mois pour assurer une réelle carence locale en 1,25-<p>dihydroxyvitamin D3. Nous avons ensuite traité des souris Tg-RP3 puis Tg-E7 par des doses variables<p>de CD578, un analogue « non calcimimétique » du calcitriol. Il est apparu que la dose ayant un effet<p>significatif au niveau transcriptionnel (surexpression de la 24-hydroxylase) était également la dose la<p>plus toxique, entrainant une hypercalcémie parfois létale. Le protocole principal a du être écourté en<p>raison d’un excès de mortalité. Le petit nombre d’animaux ayant survécu ne nous a pas permis de<p>conclure à une différence d’expression significative du Ki67 dans les thyroïdes de souris traitées par<p>CD578 par rapport aux souris contrôles. De nouvelles expériences devront donc être réalisées aux<p>doses les moins toxiques, administrées sur une plus longue période et sur un plus grand nombre<p>d’animaux, afin d’augmenter la probabilité d’observer un effet sur la prolifération, voire la<p>différenciation tissulaire.<br>Doctorat en Sciences médicales<br>info:eu-repo/semantics/nonPublished
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Pullyblank, Anne Maria. "Evaluation of the role of monoclonal antibodies m17-1A, c17-1A and cSF25 in antibody-dependent cell-mediated cytotoxicity and an exploration of the possible mechanisms of action." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268015.
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Rodrigues, Laura. "Nanoparticules polymères ciblant le récepteur CXCR3 : élaboration et évaluation sur modèles de tumeur." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0104/document.
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La thèse présentée porte sur l’élaboration de nanoparticules polymères fonctionnalisées par le ligand SCH546738 afin de cibler le récepteur CXCR3 surexprimé sur les cellules cancéreuses. La synthèse des copolymères à blocs Poly(triméthylène carbonate)-b-Poly(éthylène glycol) (PTMCb- PEG) et PTMC-b-PEG-SCH546738, puis leurs auto-assemblages dans l’eau avec des pourcentages différents de l’un par rapport à l’autre et enfin l’activité biologique de ces nanoparticules in vitro ont été réalisés. Une série de PTMC-b-PEG de fraction hydrophile massique f différentes (entre 34 et 6%) ont été obtenus par polymérisation par ouverture de cycle (ROP) du monomère triméthylène carbonate (TMC) amorcée par un PEG (MW= 2000 g/mol). Les études d’auto-assemblage ont montré que la fraction hydrophile était liée à la morphologie des objets obtenus (micelles et vésicules) et que la taille et la morphologie pouvaient être modulées en fonction du protocole utilisé. Des PTMC-b-PEG-SCH546738 ont été obtenus par couplage convergent entre le PEG-SCH546738 et le bloc PTMC. Le co auto-assemblage entre les copolymères fonctionnalisés et non fonctionnalisés a été réalisé par nanoprécipitation contrôlée par un système de microfluidique qui permet d’obtenir des polymersomes monodisperses de tailles contrôlées. Le pourcentage molaire de SCH546738 en surface des polymersomes a été fixé à 5, 10 et 20 % et à l’aide d’une nanoparticule contrôle ces échantillons ont pu être testés in vitro sur cellules HEK 293 et U87 surexprimant le CXCR3-A. L’influence du ligand et son pourcentage sur l’internalisation des nanoparticules à différents temps et sur le blocage des voies de signalisation des cellules cancéreuses ont été observés<br>This thesis deals with the elaboration of polymeric nanoparticles functionalized by the ligand SCH546738 to target the CXCR3 receptor overexpressed in human healthy or tumoral cells. Poly(trimethylene carbonate-b-Poly(ethylene glycol) (PTMC-b-PEG) blocks copolymers and PTMC-b-PEG-SCH546738 synthesis, then their self-assembly with different ratios in water, and finally biological activity in vitro of these different nanoparticles were studied. A serie of PTMC-b-PEG with different hydrophilic mass fractions f (between 34 and 6%) were obtained by ring opening polymerization (ROP) of trimethylene carbonate (TMC) initiated by a block PEG (MW: 2000 g/mol). Self-assembly studies showed that the hydrophilic mass fraction was related to the morphology of the nano objects (micelles and vesicles) and that size and morphology of nano objects can be changed by the self-assembly protocol. PTMC-b-PEG-SCH546738 were obtained by the convergent coupling between PEG-SCH546738 and PTMC block. The co self-assembly of functionalized and not functionalized copolymers was done by nanoprecipitation controlled by a microfluidic system that allows monodisperse polymersomes with controlled size to be produced. The molar percentage of SCH546738 at the surface of polymersomes was fixed at 5, 10 and 20 %, and with the control nanoparticle, these samples were tested in vitro on HEK 293 and U87 cells overexpressing the CXCR3-A. The influence of the ligand and its percentage on nanoparticles internalization and signaling pathways blocking on cells were analyzed
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Behrang, Yasmin [Verfasser]. "Etablierung und Charakterisierung eines neuen humanen, hochdifferenzierten und funktionell-aktiven Tumormodells eines pankreatischen neuroendokrinen Tumors : Establishment and Characterization of a Novel Well-differentiated and Functionally Active Human Pancreatic Neuroendocrine Tumor Model / Yasmin Behrang." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1221084143/34.
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Catrina, Anca Irinel. "Studies of molecular mechanisms of action of TNF antagonists in rheumatoid arthritis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-102-4/.
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Turner, Penelope A. "Biologically active kigamicin analogues by sequential palladium catalysed C-O and C-C bond construction." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/56392/.
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This thesis describes the study of the synthesis and biological evaluation of analogues of the kigamicin natural products. Chapter One gives a background to pancreatic cancer and explains the anti-austerity strategy for new therapeutics. It then describes the kigamicins and their biological activity, focusing on why they are thought to be clinically applicable. Other structurally related, tetrahydroxanthone containing, natural products are also discussed. Chapter Two focuses on the synthesis of the tetrahydroxanthone nucleus. Existing methodology is initially utilised, before exploring formation of the tetrahydroxanthone using milder, metal catalysed routes. Copper and palladium are both explored for this transformation and an underlying uncatalysed process is revealed and fully investigated. This methodology is extended to tandem catalysis for the synthesis of 7-arylated tetrahydroxanthones through combination of this chemistry with Suzuki-Miyaura couplings. Examples of Sonogashira and Heck couplings as well as alternative substitution patterns, are also presented. Chapter Three discusses the attempted synthesis of the fused rings of the kigamicins. Our efforts towards suitable substrates are detailed. Chapter Four outlines the anti-austerity assays established to evaluate the potency and selectivity of analogues synthesised in Chapter Two. Kigamicin C is tested in this assay to compare with literature values and validate our assay. The potency and selectivity of our analogues are reported and compared to the natural product. The anti-austerity effect of kibdelone C and analogues, is investigated for the first time. Attempted isolation of the natural product is also described. Chapter Five details the experimental procedures and characterisation data for the novel compounds produced.
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Gonczy, Blanka. "Design, synthesis and biological evaluation of nucleotide pro-drugs centred on clinically active anticancer nucleosides." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/99376/.
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Cancer is one the on the leading causes of mortality in world, causing 8.2 million deaths in 2012. In light of these statistics, the battle against cancer is ongoing. Nucleoside analogues are a major force in cancer chemotherapy. However, one problem accompanying nucleoside-based therapy is drug resistance, due to the abrogation of mechanisms that are crucial to their transformation to their bioactive metabolites (nucleoside phosphates). The ProTide technology was designed to overcome the limitations associated with nucleoside analogues. The technology enables the delivery of the nucleoside monophosphate into the cell by passive diffusion. Work in this thesis details the application of the aryloxyphosphoramidate and phosphorodiamidate pronucleotide approaches on potent anticancer purine and pyrimidine nucleoside analogues. The work presented in this thesis shows that: I. ProTides of 5-fluorouracil- 2’deoxyuridine (FUDR), the deoxyribonucleoside derivative of 5-fluorouracil (5- FU), were able to overcome several important cancer resistance mechanisms, including active transport and nucleoside kinase mediated activation, illustrated by a potent cytotoxic action in different cancer cell lines. Eight potential candidates were synthesised in large-scale and underwent a comprehensive lead selection, identifying NUC3373 for clinical trials, to start in 2015; II. The successful application of ProTide and phosphorodiamidate technologies to 6-thioinosine and 6-thioguanosine did not improve their activity nor did it help in clarifying their mechanism of action. 6-S-Methyl-thioinosine and its ProTides exhibited far greater efficacy compared to 6-thioinosine; III. Application of the ProTide technology on cladribine provided IV proof of the enhanced potencies of 3’-ProTide derivatives over their 5’-counterparts; IV. 2’-deoxy-5-azacytidine (Decitabine) ProTides did not exhibit an improvement in activity compared to the parent nucleoside in different cell models of cancer; V. The bioactivation mechanisms of ProTides using enzymatic assays were successful. Based on these findings, potential avenues to further explore are the cladribine and 6-S-methyl-thioinosine ProTide families, with the hope to identify new clinical candidates.
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Cancel, Jean-Charles. "Etude des mécanismes moléculaires conférant aux cellules dendritiques XCR1+ leurs capacités à activer les lymphocytes cytotoxiques au cours d'une réponse antivirale et antitumorale." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0438.
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Les cellules dendritiques (DC) sont les sentinelles de l'organisme. Elles sont constituées de plusieurs sous-populations, chacune possédant des caractéristiques et fonctions propres. Les DC conventionnelles de type 1 (cDC1) sont l'une de ces sous-populations. Ces cellules sont identifiables dans tous les tissus, et quelle que soit l'espèce par l'expression d'un marqueur unique: le récepteur de chimiokine XCR1 (Crozat et al. 2010;2011). Les cDC1 possèdent des fonctions uniques qui promeuvent l'activation des lymphocytes, notamment via la présentation croisée d'antigènes exogènes (Cancel et al. 2019). Hormis la présentation croisée, les mécanismes régissant les interactions entre cDC1 et lymphocytes restent encore mal caractérisés. L'objectif de ma thèse était de déterminer les voies de signalisation permettant aux cDC1 de dialoguer avec les lymphocytes, à l'homéostasie, lors d'infections ou en contexte tumoral. J'ai identifié plusieurs signaux jouant un rôle dans ce dialogue: la production par les cDC1 de CXCL9 possédant des propriétés attractrices des lymphocytes T, la transprésentation par les cDC1 d'IL-15 en complexe avec l'IL15Rα régulant l'homéostasie des lymphocytes, et enfin le récepteur de chimiokine XCR1 participant à l'attraction des cDC1 par les lymphocytes sécrétant son ligand XCL1 (Yoshida et al. 1998). D'autre part, j'ai aussi montré que selon les chimiokine présentes dans la tumeur, les cDC1 pouvaient être bénéfiques ou délétères pour l'hôte. Ma thèse pose les bases de nouvelles perspectives thérapeutiques visant à utiliser les propriétés des cDC1 comme compléments aux immunothérapies actuellement utilisées en clinique chez des patients atteints de cancers<br>Dendritic cells (DC) are the body's sentinels. DCs are composed of several sub-populations, each of which has its own characteristics and functions. Conventional Type 1 DCs (cDC1) represent one of these sub-populations. These cells are identifiable in all tissues, regardless of species, by the expression of a unique marker: the XCR1 chemokine receptor (Crozat et al. 2010; 2011). cDC1 have a range of unique functions that promote lymphocyte activation, including the cross presentation of exogenous antigens (Cancel et al. 2019). Apart from cross presentation, the mechanisms governing interactions between cDC1 and lymphocytes are still poorly characterized. The objective of my thesis was to determine the signaling pathways that allow cDC1 to interact with lymphocytes, at homeostasis, during infections or in a tumor context. I have identified several signals that play a role in this dialogue: the production by cDC1 of CXCL9, a chemokine with T cell attracting properties, the transpresentation by cDC1 of IL-15 in complex with IL15Rα regulating lymphocyte homeostasis, and finally the XCR1 chemokine receptor involved in attracting cDC1 by lymphocytes secreting XCL1, its ligand (Yoshida et al. 1998). On the other hand, I have also shown that depending on the chemotactic molecules present in the tumor, cDC1 may be beneficial or harmful to the host. My thesis work lays the foundation for new therapeutic perspectives to use cDC1 properties as a complement to immunotherapies currently used in clinical practice in patients with cancers
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Alshaer, Walhan. "Fonctionnalisation de liposomes par des aptamères pour le ciblage actif des cellules cancéreuses." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS055/document.
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Dans ce travail, nous avons pu sélectionner par la méthode SELEX un aptamère à ARN modifié, appelé Apt1, qui se lie avec une haute affinité au récepteur CD44. L'aptamère sélectionné a été modifié avec par des 2'-F-pyrimidines afin d’augmenter sa stabilité vis-à-vis des nucléases pour une application thérapeutique. Cet aptamère a été ensuite greffé sur des liposomes contenant des séquences de siRNA dirigées contre un gène rapporteur, dans le but d’un ciblage actif des cellules tumorales exprimant le récepteur CD44. Cette fonctionnalisation a été réalisée par la conjugaison d’un dérivé 3'-thiol de Apt1 et un dérivé maléimide de phospholipides, directement à la surface des liposomes, ou bien séparément puis par post-insertion sur les liposomes. Les liposomes ainsi formulés présentent une forte affinité pour les cellules exprimant le CD44 sans déclencher de réponse inflammatoire au sein de ces cellules. En outre, nous montrons que l'inhibition du gène rapporteur est augmentée et prolongée lorsque l’aptamère est couplé aux liposomes chargés aux siRNA, in vitro ainsi qu’in vivo sur un modèle murin orthotopique de cancer du sein. De tels vecteurs de siRNA constituent donc un outil prometteur pour le ciblage actif de tumeurs exprimant le récepteur CD44. L'étape suivante consistera charger ces vecteurs par des séquences de siRNA permettant de réprimer des oncogènes<br>In this work we succeeded to select a modified RNA aptamer, named Apt1, to bind the human CD44 receptor protein with high affinity using the Systemaic Evolution of Ligands by EXponential enrichment (SELEX) method. The selected aptamer was modified with 2'-F-pyrimidines to increase its stability against nucleases for therapeutic applications. Furthermore, we designed and characterized aptamer-functionalized liposomes loaded with siRNA molecules against a reporter gene as a model drug delivery system for the active targeting CD44-expressing tumor cells in vitro and in vivo. Such functionalization was performed by conjugation of 3'-thiol-modified Apt1 to maleimide-modified phospholipids, either on the surface of liposomes, or separately, followed by post-insertion onto liposomes. The targeted liposomes displayed high affinity for CD44-positive cells without triggering any inflammatory response within these cells. Moreover, we show that a higher and prolonged inhibition of the targeted gene can be achieved when siRNA-loaded liposomes are functionalized by the aptamer, both in vitro and in vivo on a murine orthotopic breast cancer model. Such a delivery system may thus be a useful tool for the active targeting of CD44-expressing tumors and silencing oncogenes in vivo
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Ablin, Richard, Howard Kynaston, Malcolm Mason, and Wen Jiang. "Prostate transglutaminase (TGase-4) antagonizes the anti-tumour action of MDA-7/IL-24 in prostate cancer." BioMed Central, 2011. http://hdl.handle.net/10150/610197.
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BACKGROUND:Transglutamiase-4 (TGase-4), also known as prostate transglutaminase, belongs to the TGase family and is uniquely expressed in the prostate gland. The functions of this interesting protein are not clearly defined. In the present study, we have investigated an unexpected link between TGase-4 and the melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24), a cytokine known to regulate the growth and apoptosis of certain cancer and immune cells.METHODS:Frozen sections of normal and malignant human prostate tissues and human prostate cancer (PCa) cell lines PC-3 and CA-HPV-10, cell lines expressing low and high levels of TGase-4, and recombinant MDA-7/IL-24 (rhMDA-7/IL-24) were used. Expression construct for human TGase-4 was generated using a mammalian expression vector with full length human TGase-4 isolated from normal human prostate tissues. PC-3 cells were transfected with expression construct or control plasmid. Stably transfected cells for control transfection and TGase-4 over expression were created. Similarly, expression of TGase-4 in CA-HPV-10 cells were knocked down by way of ribozyme transgenes. Single and double immunofluorescence microscopy was used for localization and co-localization of TGase-4 and MDA-7/IL-24 in PCa tissues and cells with antibodies to TGase-4<br>MDA-7/IL-24<br>IL-20alpha<br>IL-20beta and IL-22R. Cell-matrix adhesion, attachment and migration were by electric cell substrate impedance sensing and growth by in vitro cell growth assay. A panel of small molecule inhibitors, including Akt, was used to determine signal pathways involving TGase-4 and MDA-7/IL-24.RESULTS:We initially noted that MDA-7 resulted in inhibition of cell adhesion, growth and migration of human PCa PC-3 cells which did not express TGase-4. However, after the cells over-expressed TGase-4 by way of transfection, the TGase-4 expressing cells lost their adhesion, growth and migratory inhibitory response to MDA-7. On the other hand, CA-HPV-10 cells, a cell type naturally expressing high levels of TGase-4, had a contrasting response to MDA-7 when compared with PC-3 cells. Inhibitor to Akt reversed the inhibitory effect of MDA-7, only in PC-3 control cells, but not the TGase-4 expressing PC-3 cells. In human prostate tissues, TGase-4 was found to have a good degree of co-localization with one of the MDA-7 receptor complexes, IL-20Ra.CONCLUSION:The presence of TGase-4 has a biological impact on a prostate cancer cell's response to MDA-7. TGase-4, via mechanism(s) yet to be identified, blocked the action of MDA-7 in prostate cancer cells. This has an important implication when considering the use of MDA-7 as a potential anticancer cytokine in prostate cancer therapies.
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Estornes, Yann. "Propriétés invasives de cellules tumorales coliques humaines : rôle de la famille ADF / cofiline, proteines régulatrices du cytosquelette d'actine." Lyon 1, 2007. http://www.theses.fr/2007LYO10132.
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Evans, Ashley L. "ID4 as a tumor suppressor: mechanism of action of ID4 in prostate cancer." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2013. http://digitalcommons.auctr.edu/dissertations/743.
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Id proteins are members of basic helix-loop-helix family. However, Id proteins lack the basic binding domain, which prevents DNA binding, and thereby regulates transcription. There are four members in the Id protein family termed Idl-4. In prostate cancer the expression of Idl and Id3 is high, whereas member Id4 expression is low. Decreased expression of Id4 is due to promoter hypermethylation in prostate cancer as well as many other cancers. This observation led us to hypothesize that Id4 acts as a tumor suppressor in prostate cancer. Furthermore, evidence suggests ectopic Id4 expression in metastatic prostate cancer cell line DU145 induced cell cycle arrest, apoptosis, and senescence. In this study, we expanded on these earlier studies to demonstrate that gain of Id4 attenuates cancer phenotype whereas loss of Id4 promotes cancer phenotype in prostate cancer cell lines DU145 and LNCaP, respectively. Upon over-expression of Id4 in DU145 cells (DU145+W4), there was an increase in apoptosis, due to decreased mitochondrial membrane potential (MMP) and increased expression of pro-apoptotic markers (PUMA, BAX, and p21). Inversely, silencing of Id4 in LNCaP cells (LNCaP-Id4) led to decreased apoptosis due to an intact mitochondrial membrane and decrease in the expression of pro-apoptotic markers (PUMA, BAX, and p21). Since BAX, PUMA, and p21 are direct transcriptional targets of p53, these results therefore prompted us to investigate the effect of Id4 on expression and activity of p53. LNCaP cells express wild-type p53. DU145 cells harbor mutant p53 (P223L and V274F), which lies within the DNA binding domain and abrogates p53 transcriptional activity. DU145 cells also express high levels of p53, due extended half-life. Surprisingly, there was decreased expression of p53 in DU145+Id4 cells associated with nuclear localization indicating enhanced transcriptional activity. We investigated p53 DNA binding and transcriptional activity. We determined that mutant p53 in DU145+Id4 cells was transcriptionally active evident by increased luciferase activity and binding of p53 to the promoters of its targets. In LNCaP-Id4, p53 expression was decreased which resulted in decreased p53 transcriptional activity and decreased DNA binding ability. The data suggested that Id4 can restore mutant p53 activity, which is a significant observation. Our results also suggest that Id4 promotes the assembly of a macromolecular complex involving CBP/p300 that results in acetylation of p53 at K373, a critical post-translational modification required for its biological activity. Loss of Id4 in LNCaP cells also abrogated wild type p53 DNA binding and transcriptional activity with concomitant loss of CBP/p300 requirement and decreased acetylation. In conclusion, we demonstrated that loss of Id4 promotes cancer phenotype in LNCaP cells. We also demonstrated that the tumor suppressor activity of Id4 is in part through regulation of CBP/p300 dependent acetylation and function of p53.
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Alba, Castellón Lorena 1984. "Snail1 expression in mesenchimal cells promotes tumorigenesis and tumor progression." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/403887.
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Snail transcription factor 1 triggers epithelial to mesenchymal transition. In cancer, this process provides tumoral epithelial cells with invasive characteristics. In this thesis, we demonstrated that the function of Snail1 in fibroblasts and mesenchymal stem cells (MSCs) also contributes to tumor progression. In tumors with a mesenchymal origin, expression of Snail1 in oncogenic MSCs is needed to maintain their tumorigenic capacity and is required in vivo for tumor formation. Therefore, its deletion results in the absence of tumors. In tumors with an epithelial origin, we demonstrated that Snail1 expression in stromal fibroblasts is required to promote tumor cell invasion. Fibroblasts are activated in a Snail1-dependent manner by factors such as TGF- released by epithelial tumor cells. As response, fibroblasts secrete prostaglandin E2 which contributes to tumor invasion. Consequently, depletion of Snail1 in in vivo cancer models reduces the invasion to adjacent tissues and decreases metastasis. These results suggest a key role for Snail1 in tumor progression that is not limited to its expression in epithelial cells.<br>El factor de transcripción Snail1 es necesario para iniciar la transición epitelio-mesénquima. En cáncer, este proceso provee a las células epiteliales tumorales con características invasivas. En esta tesis demostramos que la función de Snail1 en fibroblastos y en células madre mesenquimales (MSCs) también contribuye a la progresión tumoral. En tumores de origen mesenquimal la expresión de Snail1 en MSCs es necesaria para mantener sus capacidades tumorigénicas e in vivo es necesaria para la formación del tumor. En tumores de origen epitelial, la expresión de Snail1 en los fibroblastos del estroma es necesaria para promover la invasión de las células tumorales. Los fibroblastos son activados de manera dependiente de Snail1 gracias a factores liberados por las células epiteliales del tumor; por ejemplo TGF-. Uno de los efectos de esta activación es la secreción de prostaglandina E2 la cual contribuye a la invasión tumoral. En consecuencia, la depleción de Snail1 en modelos tumorales in vivo reduce la invasión a tejidos adyacentes y disminuye la aparición de metástasis. Estos resultados sugieren un rol clave de Snail1 durante la progresión tumoral que no está limitado a su expresión en células epiteliales.
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Collins, Laura. "The Mechanism of Action of a New Class of Nucleoside Analogs Targeting Gastrointestinal Tumours." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38845.
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Gastrointestinal malignancies such as liver and pancreatic cancers are the deadliest due to late detection and drug resistance. Nucleoside analogues, like Gemcitabine, are the conventional therapy despite their little impact on survival and off-target toxicity. A novel class of nucleoside analogues able to evade drug resistance mechanisms has been developed by the Guindon group and biologically screened in our lab. Some of these proprietary molecules were further equipped with a lipoate moiety designed to target cancer cell metabolism. LCB2151 and LCB2179 have emerged as the lead molecules in this class, with an IC50 of 10-15 µM in the Gemcitabine-resistant human pancreatic (Capan-2 & Panc-1) cancer cell lines. The focus of this project is deciphering the cellular mechanisms activated by LCB2151 in these pancreatic cancer lines. A series of biased molecular approaches, like gene expression profiling, and unbiased large throughput proteomic and metabolomics analyses were applied to identify potential targets and affected pathways. Results collectively show that LCB2151 evades drug resistance mechanisms, increases pro-apoptotic markers and impairs mitochondrial respiration as early as 6 hours posttreatment. Furthermore, MS/MS analyses reveal that LCB2151 alters the levels of several metabolites in the central carbon metabolism pathway and identifies the citric acid cycle enzyme α-ketoglutarate dehydrogenase as a potential molecular target of LCB2151. Understanding the exact mechanism of action of our lead molecule along with extensive testing on murine cancer models, will surely pave its way to clinical testing and evaluation.
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Giacalone, Pierre Ludovic. "Action de l'adrénomédulline dans le cancer épithélial de l'ovaire : relation avec les estrogènes et leurs récepteurs." Montpellier 1, 2003. http://www.theses.fr/2003MON1T004.
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Le cancer epithelial de l'ovaire est un cancer grave de la femme menopausee. Le traitement actuel associant de facon ideale une chirurgie la plus radicale et une chimiotherapie adjuvante ne permet une remission de courte duree dans les formes avancees. L'adrenomedulline est un peptide multifonctionnel dont les effets sur la carcinogenese se retrouvent a plusieurs niveaux : la proliferation tumorale, la stimulation de l'angiogenese et de la motilite cellulaire et l'inhibition de l'apoptose cellulaire. Enfin, les estrogenes, laisses de cote dans le cancer ovarien, voient leurs roles reevalues a la lumiere de travaux experimentaux et d'etudes epidemiologiques. Notre travail a utilise comme materiel des lignees cellulaires ovariennes d'origine humaine, des fragments tissulaires provenant de tissus ovariens normaux, de kystes et de tumeurs epitheliales. Certains de ces tissus ont ete soumis a une microdissection par rayon laser permettant d'analyser de facon separee les expressions epitheliales et stromales des genes cibles. Nous avons montre que l'estradiol etait un agent mitogene puissant et que la proliferation cellulaire sous estrogene etait significativement ralentie grace a un anticorps anti-adrenomedulline. Par technique de quantification des messagers utilisant une rt-pcr et un analyseur taqman, nous avons montre que nos cellules et nos tissus exprimaient l'arn de l'adrenomedulline, de ses recepteurs et des deux isoformes des recepteurs aux estrogenes. Par contre, l'expression de l'adrenomedulline n'etait pas regulee par les estrogenes. L'expression de l'adrenomedulline et des recepteurs aux estrogenes etait essentiellement epitheliale comme l'a montre l'analyse des fragments tissulaires disseques au laser. Enfin, nous avons montre une correlation forte entre l'adrenomedulline et les recepteurs aux estrogenes au niveau des tumeurs malignes. Ces resultats ont un premier effet immediat qui est celui de reactiver comme d'autres le role des estrogenes dans les cancers ovariens. Ils ouvrent ensuite un vaste champ d'experimentation faisant intervenir la therapie par les immunoglobulines specifiques d'une part, et les traitements par les nouvelles molecules communement appelees antiestrogenes.
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Taieb, David. "Fonction antitumorale d'ARGBP2 dans le cancer du pancreas par inhibition de l'adhésion et de la migration cellulaire." Aix-Marseille 2, 2009. http://theses.univ-amu.fr.lama.univ-amu.fr/2009AIX22027.pdf.
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Le mauvais pronostic du cancer du pancréas est dû à son extension locorégionale rapide, à la rapidité d’apparition des métastases à distance et à la faible efficacité des chimiothérapies actuelles. A ce jour, l’identification d’oncogènes ou de gènes suppresseurs impliqués dans la maladie n’a pas permis d’aboutir à des traitements efficaces. Nous avons montré qu’ArgBP2 (Arg-binding protein 2) module les évènements cellulaires impliqués dans l’invasivité de ce cancer. ArgBP2 est une protéine multiadaptatrice impliquée dans la régulation du cytosquelette d’actine. ArgBP2 contrôle l’adhérence et la migration des cellules tumorales par le biais de la régulation de WAVE-1, un activateur du complexe de nucléation de l’actine. ArgBP2 facilite l’interaction de c-Abl ou PTP-PEST avec WAVE-1, favorisant ainsi sa phosphorylation ou sa déphosphorylation. L’utilisation du double hybride chez la levure nous a permis d’identifier de nouvelles protéines interagissant avec ArgBP2, dont CIP4 (Cdc42-interacting protein–4). CIP4 interagit avec ArgBP2 et WAVE-1. CIP4 augmente aussi la phosphorylation de WAVE-1 par c-Abl et agit donc en synergie avec ArgBP2. La création d’un mutant d’ArgBP2 sur 5 résidus tyrosines a montré le rôle essentiel de la phosphorylation d’ArgBP2 dans la régulation de sa fonction. L’identification de nouveaux complexes multiprotéiques impliqués dans la migration cellulaire pourrait aboutir au développement de cibles thérapeutiques attractives dans le cancer du pancréas.
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Watts, Sam. "The assessment and management of anxiety and depression in prostate cancer patients being managed with active surveillance." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/374751/.
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CHOKRI, MOHAMED. "Controle de l'activation du macrophage murin in-vitro et in-vivo : effet antitumoral et action de differents immunostimulants." Université Louis Pasteur (Strasbourg) (1971-2008), 1989. http://www.theses.fr/1989STR13061.
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Mise au point d'une methode pour la proliferation de macrophages murins residents en presence de cellules nourricieres. Etablissement et caracterisation de differentes lignees cellulaires de macrophages. Utilisation de ces macrophages actives pour une immunotherapie de tumeurs solides chez la souris, comparaison avec des immunomodulateurs comme les interferons et le facteur de necrose tumorale
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Adigun, Risikat Ajibola. "Insight into the Reactivity of Metastasis Inhibitor, Imidazolium trans-[tetrachloro (dimethyl sulfoxide)(imidazole)ruthenate(III)], with Biologically-active Thiols." PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/378.
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Imidazolium trans-[tetrachloro (dimethyl sulfoxide)(imidazole)ruthenate(III)], NAMI-A, is an experimental metastasis inhibitor whose specific mechanism of activation and action remains to be elucidated. In the nucleophilic and reducing physiological environment; it is anticipated that the most relevant and available reductants upon introduction of NAMI-A as a therapeutic agent will be the biologically-relevant free thiols. The kinetics and mechanisms of interaction of NAMI-A with biologically-active thiols cysteamine, glutathione, cysteine and a popular chemoprotectant, 2-mercaptoethane sulfonate (MESNA) have been studied spectrophotometrically under physiologically-relevant conditions. The reactions are characterized by initial reduction of NAMI-A with simultaneous formation of dimeric thiol and subsequent ligand exchange with water to various degrees as evidenced by Electospray Ionization Mass Spectrometry. Stoichiometry of reactions shows that one molecule of NAMI-A reacted with one mole of thiol to form corresponding disulfide cystamine, dimeric MESNA, oxidized glutathione and cystine. Observed rate constants, ko, for the reaction of NAMI-A with cysteamine, MESNA, GSH and cysteine were deduced to be 6.85 + 0.3 x 10-1, 9.4 + 0.5 x 10-2 , 7.42 + 0.4 x 10-3 and 3.63 + 0.3 x 10-2 s-1 respectively. Activation parameters determined from Arrhenius plots are indicative of formation of associative intermediates prior to formation of products. A negative correlation was obtained from the Brønsted plot derived from observed rate constants and the pKa of the different thiols demonstrating significant contribution of thiolate species towards the rate. In conclusion, interactions of NAMI-A with biologically-active thiols are kinetically and thermodynamically favored and should play significant roles in in vivo metabolism of NAMI-A.
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Wang, Suwei. "Mechanisms of Cr(VI)-induced carcinogenesis the involvement of reactive oxygen species and signal transduction pathway /." Morgantown, W. Va. : [West Virginia University Libraries], 2001. http://etd.wvu.edu/templates/showETD.cfm?recnum=1803.
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Thesis (Ph. D.)--West Virginia University, 2001.<br>Title from document title page. Document formatted into pages; contains viii, 124 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.
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Menezes, Michelle dos Santos. "O papel do jaspamídeo na dinâmica do citoesqueleto de actina das células de melanoma: relação com migração e invasão." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-19032012-145318/.
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No processo de metástase os movimentos de migração e invasão tem um papel essencial e em ambos a função dos microfilamentos é de grande importância. Neste contexto, o presente trabalho buscoui analisar os efeitos da droga jaspamídeo e após a determinação das concentrações de IC50 para as linhagens HT144 e NGM foram estudados os efeitos da droga. Os tratamentos mostraram que o fármaco atua desorganizando o citoesqueleto de modo dependente de sua concentração. Os ensaios de ferida mostraram diminuição da taxa de fechamento da área livre após os tratamentos e os ensaios de migração com placas de transwell mostraram que os grupos tratados sofrem aumento desse parâmetro. Nos ensaios de invasão com câmara de Boyden o tratamento mostrou-se efetivo apenas para a célula NGM quando tratadas com 75 nM de jaspamídeo e 30 <font face=\"Symbol\">mM de Y-27632. Quanto à migração, a linhagem NGM não completava este processo quando tratada com as concentrações do IC50 e do IC50/2 acrescido de Y-27632 e a linhagem HT144 apresenta aumento deste parâmetro quando tratado com jaspamídeo e 200 <font face=\"Symbol\">mM de NSC23766.<br>Many signaling ways are involved in metastasis and the cellular migration and invasion are important in this context. The role of microfilaments is essential in mesenchymal and amoeboid migration. In this context, the present work aimed to analyze the effects of the drug jaspamide and. after the determination of the IC50 concentrations for the HT144 and NGM cell lines, the effects of the treatment with jaspamide were studied. The wound assays indicated a decrease in the free area after the treatments, and the migration assays with transwell showed that, after the inoculation with the drug, the cells increased the process of migration. In the invasion assays with Boydens chamber, the treatment with jaspamide was effective only in NGM cells, when they are treated with 75 nM of the drug plus 30 <font face=\"Symbol\">mM of Y-27632. Regarding the migration process, the NGM cell line did not show movement when treated with the IC50 concentration and the IC50/2 concentration plus Y-27632, and the HT144 cell line increases this parameter when treated with jaspamide and 200 <font face=\"Symbol\">mM of NSC23766.
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Leite, IsmÃnia OsÃrio. "Estudo de fase I da vacina anticÃncer HASUMI." Universidade Federal do CearÃ, 2004. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=22.
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FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico<br>The Hasumi vaccine (VH) is an imune-stimulant mode by two preparations obtained from distinctive forms, it is an assisting in a pool of tumours antigens. The assisting is taken off from calf splens and the antigen, from different forms of tumor. The VH is a sterile uncoloured liquid, conditioned in 0,5mL glass ampoules, separately. The present research aimed to evaluate, throughout a Phase I study, the security of VH, as well as the comprehension of its action mechanism. The clinical experiment was conducted in 24 healthy volunteers in wich the VH was given subcutaneously every 5 days during 2 months, accomplishing an amount in wich the two first ones were given in the hospital. Before the first administration, all the voluteers did the Prick test, to evaluate the possibility of reacting to hipersensibility. After that they were submit to clinical and laboratorial evaluation (hemogram, biochemical, urine extract and parasitological excrements exams, sorology to B and C hepatitis, HIV, FAN, reumatoidic factor, C3, CD3, CD4, CD8, IgA, IgG, IgE, IgM, PSA, CEA, AFP and HCG-beta). The planning of the experiment also had the repetition of such exams after the 3th, 6th and the 12th doses, as well as in the after-study 30 days after the last dose. By hte and of the study, significant adverse events were not observed. Therefore, in the last dose and within the stabilished treatment period of this experiment, the VH was shown to be safe and with no toxity.<br>A Vacina Hasumi (VH) à um imuno estimulante constituÃdo por duas preparaÃÃes obtidas de formas distintas, sendo um adjuvante e um pool de antÃgenos tumorais. O adjuvante à retirado de cÃlulas de baÃo de bezerros e o antÃgeno, de diversas formas de tumor. A VH à um lÃquido incolor estÃril, acondicionado em ampolas de vidro, no volume de 0,5mL, separadamente. O presente trabalho objetivou avaliar, atravÃs de um Estudo de Fase I, a seguranÃa da VH, bem como a compreensÃo do seu mecanismo de aÃÃo. O ensaio clÃnico foi conduzido em 24 voluntÃrios sadios nos quais a VH foi administrada por via subcutÃnea a cada 5 dias durante 2 meses, perfazendo um total de 12 administraÃÃes, sendo as 2 primeiras em regime de internamento hospitalar. Antes da primeira administraÃÃo, todos os voluntÃrios realizaram o prick teste, para avaliar a possibilidade de reaÃÃo de hipersensibilidade, apÃs o que, foram submetidos a avaliaÃÃes clÃnica e laboratorial (hemograma completo, bioquÃmica, sumÃrio de urina, parasitolÃgico de fezes, sorologia para hepatite B e C, HIV, FAN, fator reumatÃide, C3, CD3, CD4, CD8, IgA, IgG, IgE, IgM, PSA, CEA, AFP, Beta HCG). O planejamento do experimento compreendeu tambÃm a repetiÃÃo das avaliaÃÃes apÃs a 3a, 6a e a 12a doses e no pÃs-estudo, 30 dias apÃs a Ãltima dose. Ao final do estudo nÃo foram observados eventos adversos significantes. Portanto, na dose e no tempo de tratamento estabelecidos neste ensaio, a VH mostrou-se segura e nÃo apresentou toxicidade.
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LEBEAU, JEROME. "Alterations genetiques dans les tumeurs du sein : recherche d'oncogenes actives et de genes a expression deregulee." Paris 6, 1990. http://www.theses.fr/1990PA066577.
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Le travail presente dans cette these comporte trois chapitres distincts: 1. L'etude de l'amplification du gene du recepteur de l'egf dans une lignee cellulaire humaine de carcinome du sein, la lignee bt20. 2. Le clonage moleculaire de 25kbp en amont de l'exon 0 de l'oncogene humain k-ras provenant d'une lignee cellulaire tumorale mammaire, la lignee h-466b. 3. La mise en evidence de la surexpression constitutive d'une proteine de choc thermique: la hsp89alpha apres transformation de la lignee cellulaire mammaire hbl100 par un oncogene h-ras active
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GIRAULT, VERONIQUE. "Action de la chloroquine sur la secretion du tumor necrosis factor alpha et la survie dans le choc septique de la souris." Lyon 1, 1994. http://www.theses.fr/1994LYO1M126.
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Svangård, Erika. "Cytotoxic Cyclotides : Structure, Activity, and Mode of Action." Doctoral thesis, Uppsala universitet, Institutionen för läkemedelskemi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6028.
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Cyclotides are small cyclic plant proteins, and this thesis addresses their cytotoxic structure-activity properties and their mode of action on human cancer cell lines. Cyclotides were isolated from Viola odorata and Viola tricolor; three novel cyclotide sequences and two known sequences, but of new origin, were identified using mass spectrometry, amino acid analysis, and Edman degradation. The cyclotide structure includes three disulphide bonds in a knotted arrangement, which forces hydrophobic amino acid residues to be exposed on the surface of the molecule; 3-D homology models of cyclotides have revealed an amphipathic surface and charged residues located at similar positions in the molecules. The charged amino acid residues were shown to play a key role in the cytotoxicity of the cyclotide cycloviolacinO2 on a human lymphoma cell line. Methylation of Glu caused a dramatic change in cytotoxicity, lowering the potency 48 times, whereas concealing the charge of Arg with 1,2-cyclohexanedione caused virtually no change in potency. Acetylation of the two Lys caused a 3-fold reduction in potency, and masking all positive charges caused a 7-fold reduction. Additionally, disturbing the amphipathic structure by reducing and alkylating the disulphide bonds abolished the cytotoxicity. The time dependency of cytotoxicity and cell gross morphology after cyclotide exposure were investigated on the lymphoma cell line. Cells exposed to 4 µM of cycloviolacinO2 showed necrotic characteristics, such as membrane disintegration, within 5 min; a membrane disruptive effect of cycloviolacinO2 was also observed in a functional assay based on liposomes at a peptide-to-lipid molar ratio of 6.5. The anti-tumour properties of cycloviolacinO2 were evaluated on three human cancer cell lines using the hollow fibre assay in vitro and in vivo. The cyclotide exhibited potent anti-tumour activity in the micro-molar concentration range on all cell lines in vitro, but no effect on tumour growth could be established in vivo.
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Agarwal, Abhiruchi. "Nanocarrier mediated therapies for the gliomas of the brain." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39468.
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Existing methods of treating glioma are not effective for eradicating the disease. Therefore, new and innovative methods of treatment alone or in combination with existing therapies are necessary. Delivery of therapeutic agents through delivery carriers such as liposomes diminishes the harmful effects of the agent in healthy tissues and allows increased accumulation in the tumor. In addition, targeted chemotherapy using liposomes provides the opportunity for further increase in drug accumulation in tumor. However, the current targeting strategies suffer accelerated plasma clearance and are not advantageous in improving efficacy. The search for new tumor targets, novel ligands, new strategies for targeting, and particle stabilization will advance our ability to improve delivery at the tumor level while decreasing toxicity to normal tissues.
The global objective of this thesis was to improve the status of current liposomal therapy to achieve higher efficacy in tumors. Here, we show a novel mechanism to increase targeting to tumor while uncompromising on the long circulation of stealth liposomes. Long circulation is essential for passive accumulation of the nanocarriers due to EPR effect, in order to see benefits of targeting. Using phage display technique, a variety of tumor specific peptides were identified for use as targeting moieties. One potential advantage of the approach proposed here is the rapid identification of patient tumor specific peptide that evades the RES. This could lead to the development of a nanocarrier system with high avidity and selectivity for tumors. Therefore, tumor accumulation of the targeted formulations will be higher than that of non‐targeted liposomes due to increased drug retention at the tumor site and uncompromised blood residence time.In addition, it has been shown that the distribution of nanocarriers, spatially within the tumor, is limited that might further hinder the distribution of the encapsulated drug, thereby limiting efficacy. It is necessary to release the drug from within the nanocarrier to promote increased efficacy. Here, we were able to address the problem of drug diffusion within the tumor interstitium using a combination therapy employing a remotely triggered thermosensitive liposomal chemotherapeutic. We fabricated a thermosensitive liposomal nanocarrier that maintained its stability at physiological temperature to minimize toxicity to healthy cells. We, then, showed a remote triggering mechanism mediated by gold nanorods heated via NIR can help in achieving precise control over the desired site for drug release. These strategies enabled increased drug availability at the tumor site and contributed to tumor retardation. Additionally, we show that the synergistic therapy employing gold nanorods and thermosensitive liposomes may have great potential to be translated to the clinic.