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Golightly, L. "Trypanosmoma brucei : Studies on the uptake and effects of daunorubicin and daunorubicin carrier preparations." Thesis, University of Sunderland, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375648.
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Hardman, Mark Alan. "Design of potential antiprotozoal daunorubicin derivatives." Thesis, De Montfort University, 1985. http://hdl.handle.net/2086/10737.
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Daunorubicin is an antitumour antibiotic which is highly active against the sleeping sickness parasite Trypanosoma rhodesiense in vitro, but which lacks in vivo activity. The object of this work was to modify daunorubicin so as to promote in vivo activity, and to study the mechanism by which daunorubicin is trypanocidal. A series of daunorubicin analogues, and derivatives in which daunorubicin was linked to a macromolecular carrier (known as daunorubicin conjugates) were prepared, and tested against trypanosome infected mice. Only daunorubicin conjugates in which drug was linked to the carrier by glutaraldehyde, were active. Treatment with these conjugates increased the survival time of infected mice from three days to as long as eleven days, and temporarily cleared parasites from the bloodstream of infected animals. Conjugates with other types of linkage were inactive. A fluorescence assay method was developed to measure drug release from conjugates. Investigation revealed that glutaraldehyde linked conjugate released about 20% of bound drug over a 2-3 hour period when incubated in murine plasma. In contrast, inactive conjugates either released bound drug very rapidly, or were stable to drug release. Daunorubicin is known to possess several potentially cytotoxic mechanisms of action, the most important being intercalation into the DNA double hel~x and stimulation of superoxide radical formation. In order to discover the contribution of these mechanisms to trypanocidal activity, the trypanocidal potency of a series of daunorubicin analogues was assessed in vitro. The ability of these analogues to intercalate into DNA and to stimulate lipid peroxidation and oxygen consumption was also assessed. The results were used to explore the relationship between these mechanisms and trypanocidal activity. These studies indicate that ability to bind to DNA is important in conferring trypanocidal activity on this group of antibiotics.
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Mohammed, Lina Yousif. "Studies on daunorubicin and actinorhodin type II polyketide synthases." Thesis, University of Bristol, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.761209.
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Wattana-Amorn, Pakorn. "Studies on the actinorhodin and daunorubicin type II polyketide synthases." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441375.
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Bartels, Anna-Maria. "Durchflusszytometrische Untersuchungen zur zellulären Pharmakokinetik von freien und liposomal verkapseltem Daunorubicin." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965428001.
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Maharaj, Vanitha. "A vibrational circular dichroism study of deoxyoctanucleotides and their daunorubicin complexes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq20751.pdf.
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Bartels, Anna-Maria. "Durchflußzytometrische Untersuchungen zur zellulären Pharmakokinetik von freien und liposomal verkapseltem Daunorubicin." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2002. http://dx.doi.org/10.18452/14780.
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In dieser Arbeit wurde die zelluläre Pharmakokinetik mit den Teilaspekten Invasion, Evasion und intrazellulärer Verteilung sowie die Apoptoseinduktion als Parameter der Pharmakodyna- mik von zwei Anthrazyklinen, dem freien und liposomal verkapseltem Daunorubicin unter- sucht. Die Versuche wurden anhand einer T-lymfatischen Zelllinie, den CEM-Zellen, durchgeführt. Mittels Durchflußzytometer und konfokaler Lasermikroskop wurde die intrazelluläre Fluoreszenz gemessen, die der intrazellulären Konzentration entsprach. Es zeigte sich, dass freies Daunorubicin anfangs deutlich schneller in die Zellen einströmte als liposomal verkapseltes Daunorubicin und früher die maximale Konzentration erreichte. Über eine längere Versuchszeit kam es aber zu einer Angleichung der maximal erreichten Konzen- trationen. Der Invasionsverlauf von Daunoxome verlief sigmoidförmig, während Daunorubi- cin einer Sättigungskinetik folgte. Der Invasionsverlauf beider Anthrazykline war sowohl zeit- als auch konzentrationsabhängig. Die Versuche zur intrazellulären Verteilung zeigten, dass sich beide Stoffe nach drei Stunden Inkubationszeit vom Zytoplasma in den Kern verteilten. Daunorubicin erreichte sehr schnell seine maximale Fluoreszenz im Kern. Bei Daunoxome ließ sich auch nach sechs Stunden Inkubation eine weitere Zunahme der Fluoreszenz messen. Die Untersuchungen zur Apoptoseinduktion unterstützten die Aussagen zur Invasion. Dauno- rubicin induzierte zu Anfang deutlich schneller Apoptose als Daunoxome. Über den gemessenen Versuchszeitraum kam es aber zu einer Angleichung aller Apoptoseraten. Auch hier zeigte sich eine Zeit- und Konzentrationsabhängigkeit. Die Ergebnisse der Evasionsversuche zeigten, dass Daunorubicin biphasisch und Daunoxome monophasisch ausströmte. Zusammenfassend kann gesagt werden, dass freies Daunorubicin initial eine bessere zelluläre Pharmakokinetik und damit eine höhere Zytotoxizität aufweist als liposomal verkapseltes Daunorubicin. Über die Zeit kommt es allerdings zu einer Angleichung der Zytotoxizität. Damit ist Daunoxome auf zellulärer Ebene mindestens genauso wirksam wie Daunorubicin.We studied the cellular pharmacokinetics, including uptake, intracellular distribution and efflux, and the induction of apoptosis as a parameter of pharmacodynamics of the two anthracyclines, free and liposomal encapsulated daunorubicin. We used a flowcytometer and a confocal lasermicroscope to measure the intracellular fluorescence in CEM-cells, corresponding to the intracellular concentration of the drugs. Free daunorubicin invaded initially the cells much quicker than liposomal encapsulated daunorubicin and attained earlier the maximum concentration. After the examined time daunoxome achieved the same maximum concentration as daunorubicin. The invasion of liposomal encapsulated daunorubicin followed a sigmoid course, while free daunorubicin followed a saturation kinetic. It was shown that the uptake of both anthracyclines was time- and concentration-dependent. The examinations about the intracellular distribution showed, that both drugs accumulated in the nucleus after three hours of incubation. Daunorubicin attained quickly the maximum fluorescence there, while daunoxome increased slowly for the next six hours. The results of the apoptosis induction correlated to the results of the uptake experiments. Free daunorubicin induced initially quicker apoptosis than liposomal encapsulated daunorubicin. At the end of the measured time all the apoptosis rates of both drugs appeared to be equal. It was determined that the induction of apoptosis also is time- and concentration-dependent. The efflux of daunoxome was monophasic in contrast to a biphasic decline of daunorubicin. These results indicate that free daunorubicin has improved initial cellular pharmacokinetics and therefore enhanced cytotoxicity compared with liposomal encapsulated daunorubicin. But over the examined period both got equal cytotoxicity. Therefore daunoxome is on the cellular basis at least as effective as daunorubicin.
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Battisti, Robert F. "Modifying the sugar moieties of daunorubicin overcomes P-gp-mediated multidrug resistance." Connect to resource, 2007. http://hdl.handle.net/1811/25067.
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Thesis (Honors)--Ohio State University, 2007.Title from first page of PDF file. Document formatted into pages: contains 48 p.; also includes graphics. Includes bibliographical references (p. 46-48). Available online via Ohio State University's Knowledge Bank.
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Knaust, Eva. "Experimental studies on multidrug resistance in human leukaemia : role of cellular heterogeneity for daunorubicin kinetics /." Linköping : Dept. of Medicine and Care, Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med901s.pdf.
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Masquelier, Michèle. "Leukemia chemotherapy : experimental studies on pharmacological optimisation /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-046-X/.
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Bains, Onkar Singh. "Altered metabolism of daunorubicin and doxorubicin by genetic variants of human aldo-keto and carbonyl reductases." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/29557.
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The anthracyclines, doxorubicin (DOX) and daunorubicin (DAUN) are commonly used to treat a variety of cancers. Their use is associated with life-threatening adverse events, especially chronic cardiotoxicity, in some patients. There may be a genetic basis for this variation, arising from altered metabolism by non-synonymous single nucleotide polymorphisms (ns-SNPs) in genes encoding for the aldo-keto reductase (AKR) and carbonyl reductase (CBR) enzymes, which are responsible for the biotransformation of these two drugs.
The first two studies (Chapters 2 and 3) of this thesis examined the effect of ns-SNPs in 8 AKR and 3 CBR genes on the in vitro metabolism of both anthracyclines to their major metabolites, doxorubicinol (DOXol) and daunorubicinol (DAUNol) using purified, human wild-type and genetic variant enzymes. Michaelis-Menten kinetic curves were plotted and the metabolic capacities of the wild-type and variant enzymes were compared using catalytic efficiency (kcat/Km). In the presence of DAUN, 7 AKR and 5 CBR variants exhibited significantly reduced metabolic activity while 3 AKR and 5 CBR variants demonstrated significantly reduced activity with DOX as substrate. These findings suggest that genetic variants of human AKRs and CBRs are capable of decreasing the in vitro metabolism of DOX and DAUN.
There is considerable controversy in the literature on how DAUN and DOX contribute to the variable adverse events seen in patients treated with these drugs. Some studies suggest that the toxic species are the major metabolites, DAUNol and DOXol, while others suggest the parent drug is more toxic. To study this, I examined whether a strong and consistent association exists between metabolic activity and drug toxicity among nine cell lines from different tissues (Chapter 4). My findings indicated that there is a strong, and inversely proportional, association between cytotoxicity and DAUN or DOX metabolism. Furthermore, the cell lines that were resistant to the toxic effects of these drugs had significantly greater expression of the AKRs and CBRs.
Overall, these data provide a foundation of biochemical evidence to design in vivo studies that will elucidate the role of altered metabolism by genetic variants of human AKRs and CBRs in the development of anthracycline-induced cardiotoxicity.
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Schröder, Anke. "In-vitro-Toxizität der liposomal verkapselten Anthrazykline Daunorubicin (Daunoxome) und Doxorubicin (Caelyx) auf vier verschiedenen Ewing-Sarkom-Zelllinien." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971791562.
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Turnbull, Kenneth James. "The effect of Daunorubicin on human lymphoblastic leukaemia cells and the role of ceramide and ceramide-sensitive protein kinases." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312330.
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Walczak, Robbie J. "Analyses of antibiotic biosyntheses in Streptomyces spp. : the molecular biology of nonactin biosynthesis and the novel biochemistry of daunorubicin biosynthesis /." The Ohio State University, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488205318510564.
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Chen, Wenlan. "Design, Synthesis and Immunological Evaluation of Glycoceramides and Glycoproteins for Cancer Immunotherapy & Structure Activity Relationship Study of Daunorubicin Analogues with Uncommon Sugars." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1280856149.
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Löfgren, Christina. "Pharmacological and clinical studies of new ways to improve cytostatic treatment of acute myelocytic leukemia : in vitro and in vivo studies /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-183-0/.
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Ghirmai, Senait. "Synthesis of Organic Compounds for Nuclide Therapy : Derivatives of Carboranes, 9-Aminoacridine and Anthracyclines." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4264.
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Koeniguer, Sylvie. "Mise au point d'une méthode de dosage par CLHP de la daunorubicine, de l'idarubicine et de leurs métabolites, daunorubicinol et idarubicinol, dans les prélévements pédiatriques." Paris 5, 1998. http://www.theses.fr/1998PA05P122.
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Mume, Eskender. "Radiohalogenated Compounds for Tumor Targeting : Synthesis and Radiolabeling." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4817.
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Contente, Thaís Costa. "Associação do quimioterápico daunorrubicina a uma nanoemulsão rica em colesterol: estudos de regressão tumoral e farmacocinética." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5166/tde-01022011-183828/.
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A nanoemulsão lipídica (LDE) se concentra nas células neoplásicas e pode ser utilizada como transportador de derivado lipofílico da daunorrubicina, como o Noleil- daunorrubicina (oDNR). Neste estudo, a LDE-oDNR foi preparada por homogeneização em alta pressão e sua toxicidade e atividade anti-tumoral testadas. A associação LDE-oDNR teve rendimento elevado e permaneceu estável por longo período. Em camundongosC57BL/6J, a dose máxima tolerada (DMT) foi 65 vezes maior e a DL50 48 vezes maior no tratamento LDE-oDNR comparado ao tratamento DNR comercial, resultando em alta redução da toxicidade. Em camundongos implantados com células de melanoma B16, a preparação LDE-oDNR (7,5 mol/kg) levou a redução de 59 ± 2% do crescimento do tumor comparado a redução de 23 ± 2% para o tratamento DNR comercial na mesma dose (p<0,001). A probabilidade de sobrevida teve aumento pronunciado nos animais tratados com LDE-oDNR comparado à DNR comercial (p <0,01). Além disso, apenas 30% dos animais portadores de melanoma submetidos ao tratamento com LDE-oDNR apresentaram metástases, comparado a 82% quando tratados com DNR comercial. Uma forte redução de toxicidade também foi observada pela redução da anemia e leucopenia nos animais tratados com LDE-oDNR, em comparação com DNR comercial. A preparacao LDE-oDNR foi eficaz também no quadro de trombocitose induzida por tumor. Os testes com fragmentos extraídos de tumores dos animais tratados mostraram que a LDE-oDNR foi mais eficaz na destruição das células neoplásicas comparado ao tratamento DNR comercial (9% de células viáveis com tratamento LDE-oDNR, 27% sob tratamento DNR). O estudo mostrou que o tratamento proposto com o derivado ODNR associado à nanoemulsão (LDE-oDNR) é efetivo no combate às células tumorais, seletivo, menos tóxico e melhor tolerado. Os estudos de farmacocinética e biodistribuição somam a este protocolo informações importantes relacionadas às propriedades de absorção, distribuição, metabolismo e excreção da formulação em estudo comparado à DNR comercialA lipidic nanoemulsion (LDE) that concentrates in neoplastic cells can be used as vehicle to daunorubicin lipophylic derivatives, such as N-oleyl-daunorubicin (oDNR). Here, LDE-oDNR was prepared by high pressure homogenization to test toxicity and anti-tumor activity. LDE-oDNR association yield was high and stable for long period. In mice, maximum tolerated dose was 65 and LD50 was 48-fold greater in LDE-oDNR than in commercial DNR treatment, showing very strong toxicity reduction. In melanoma B16-tumor bearing mice, LDE-oDNR (7.5 mol/Kg) reduced tumorgrowth by of 59±2%, and DNR by only 23±2% at same dose level (p<0.001). Survival was pronouncedly increased in LDE-oDNR compared to DNR treatment (p<0.01). Furthermore, the number of melanoma-bearing mice with metastasis was 30% under LDE-oDNR, compared to 82% under DNR treatment. Strong reduction of toxicity was also observed by reduction of anemia and leucopenia under LDE-oDNR, compared to commercial DNR tumor-induced thrombocytosis was more effective with LDE-oDNR than with DNR. Tests with fragments extracted from tumors of treated animals showed that LDE-oDNR was more effective in killing neoplastic cells than DNR (9% of viable cells under LDE-oDNR; 27% under DNR). The pharmacokinetics and biodistribution studies add important information to this protocol related to the properties of absorption, distribution, metabolism and excretion of the formulation under study compared to free DNR. The remarkable toxicity reduction and increase in pharmacological action supports novel LDE-oDNR as a promising weapon in cancer treatment
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Flan, Benoît. "La glycosyl-daunorubicine, un modèle d'étude pour le ciblage cellulaire de medicaments." Lille 1, 1990. http://www.theses.fr/1990LIL10059.
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L'existence dans le règne animal de lectines membranaires conduisant à l'endocytose de leur ligand et à son hydrolyse dans les lysosomes, a permis d'envisager le couplage sur le ligand d'un principe actif afin de diriger celui-ci dans l'organisme et de lui permettre d'atteindre sa cible endocellulaire après libération dans le lysosome. Afin d'envisager l'utilisation des glycannes dans le ciblage des médicaments par glycosylation, nous démontrons que ceux-ci interagissent avec le récepteur du galactose des hépatocytes de rat de la même manière que les glycoprotéines et les glycopeptides et que cette interaction entraîne leur endocytose. La mise au point de la synthèse et de la purification de conjugués de la daunorubicine ou DNR (substance anticancéreuse dont la cardiotoxicité limite l'usage en thérapeutique) à des oligosaccharides nous permet de preparer un conjugue de DNR au lactose dont l'action sur les cellules d'hépatome humain hepG2 qui possèdent le récepteur membranaire du galactose a été étudiée. Nos travaux montrent que le conjugué « lactityle-DNR » est capable de pénétrer à l'intérieur des cellules hepG2 et exerce un effet cytostatique mis en évidence par les techniques des courbes de survie, de l'incorporation de thymidine tritiée et de la cytofluorometrie de flux, comparable à celui de la DNR. Ils suggèrent la possibilité d'une interaction spécifique de ce conjugué avec le récepteur du galactose. Les intérêts potentiels de ce conjugué sont discutés
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Haidar, Julie. "Rôle du galactosylcéramide dans l'inhibition de l'apoptose induite par la daunorubicine : implication potentielle des cavéoles." Toulouse 3, 2011. http://www.theses.fr/2011TOU30119.
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La daunorubicine (DNR) est une anthracycline largement utilisée dans le traitement du cancer. Bien que pendant longtemps, on ait considéré que la cytotoxicité de la DNR était essentiellement due aux dommages induits à l'ADN, il est maintenant établi que la DNR peut tuer les cellules selon une modalité de mort programmée, l'apoptose, en activant une voie métabolique. La nature de(s) voie(s) de signalisation impliquée(s) dans l'initiation de l'apoptose induite par la DNR est importante pour la détermination de la chimiosensibilité des cellules tumorales. En effet, la DNR active une voie de signalisation apoptotique nommée " cycle de la sphingomyéline ". Cette voie consiste en l'hydrolyse de la sphingomyéline (SM) par la sphingomyélinase neutre (nSMase) et la génération du céramide (Cer). Le Cer généré a été décrit comme un médiateur lipidique qui induit l'apoptose en activant la voie JNK/AP-1 par un mécanisme dépendant des radicaux libres oxygénés (RLOs). Ainsi, logiquement, l'absence de la génération du Cer a été corrélée à la résistance à l'apoptose. Notre équipe a proposé que la voie classique de la synthèse des sphingolipides (SLs) participe à l'apoptose induite par la DNR, impliquant le recrutement de la protéine p53/p56 Lyn au niveau des rafts. Plus tard, il a été observé que les deux métabolites du Cer, le glucosylcéramide (GlcCer) et le galactosylcéramide (GalCer) pourraient être des médiateurs lipidiques pro- et anti-apoptotiques mettant en question le rôle direct du Cer. Dans cette étude, nous avons choisi d'analyser de plus près le rôle d'un de ces médiateurs (le GalCer) dans la réponse des cellules à la mort induite par la DNR. Nous démontrons que l'augmentation du taux intracellulaire de GalCer (environ 2 fois), par la surexpression de l'UDP-galactose galactosylcéramide transférase (GCT), induit la résistance des cellules HEK293T et Hela à l'apoptose induite par la DNR. Par ailleurs, nous démontrons que le GalCer est essentiellement séquestré à la membrane plasmique, en particulier dans les microdomaines membranaires " rafts ". En effet, la perturbation des rafts enrichis en GalCer sensibilise les cellules HEK-GCT et Hela-GCT à l'apoptose induite par la DNR. Ensuite, nous démontrons que le GalCer est concentré dans des structures particulières des rafts, les cavéoles. Enfin, nous démontrons l'implication du GalCer dans l'inhibition de la translocation de la protéine p53/p56 Lyn au niveau des rafts. En conclusion, nous proposons que l'apoptose induite par la DNR est modulée par une voie de signalisation qui régule négativement la translocation de Lyn au niveau des rafts, et que la conversion du Cer en GalCer est un élément essentiel de la régulation négative de la mort cellulaireThe anthracycline daunorubicin (DNR) is widely used in the treatment of many neoplastic diseases. DNR cytotoxicity was believed to be the result of drug-induced DNA damage. However, it is now established that the DNR can kill cells as a form of programmed cell death apopotis by activating a metabolic pathway. The nature of the signaling pathway(s) which initiates DNR-triggered apoptois is surely of fundamental importance in determining the chemosensitivity of the tumor cell. Indeed, the DNR activates an apoptotic signaling pathway called "sphingomyelin cycle". This pathway involves the hydrolysis of sphingomyelin (SM) by neutral sphingomyelinase (nSMase) and generation of ceramide (Cer). The Cer lipid messenger activates JNK/AP-1 module by mechanism depending on radical oxygen species. Hence, logically, the absence of Cer generation was responsible for resistance to apoptosis. We first proposed the involvement of a 'classic' sphingolipid pathway in DNR-triggered apoptosis, implicating raft-recruitment of p53/56 Lyn. We later observed that two Cer metabolites glucosylceramide and galactosylceramide (GalCer) could be the fundamental pro- and anti-apoptotic lipid mediators, therefore questioning the direct role of Cer. In this study, we elected to take a closer look at one of these potential cell death mediators GalCer. We report that increasing GalCer (approx. 2-fold) by overexpressing UDP-galactose-ceramide galactosyltransferase (GCT), in HEK293T and HeLa cells blocked DNR-induced apoptosis. Moreover, the increase in GalCer was essentially sequestered in plasma membrane. Indeed, raft disruption significantly inhibited galactosylceramide's inhibitory effect. We also provide evidence that caveolae are the membrane components implicated. In conclusion, we discuss how the regulation of daunorubicin-triggered apoptosis is mediated by a signaling pathway which negatively regulates p53/56 Lyn raft-recruitment, and is initiated post early sphingomyelin-derived ceramide production, and that the conversion of ceramide to galatosylceramide is an essential negative regulatory element of cell death
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Pagé, Brigitte. "Évaluation de la cytotoxicité de conjugués anticorps-peptide-daunorubicine sur des cellules résistantes d'un cancer ovarien." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0005/NQ39386.pdf.
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Bailly, Jean-Denis. "Caractérisation des mécanismes de résistance à la daunorubicine et à la mitoxantrone dans des cellules de leucémie aigue myéloi͏̈de de phénotype précoce." Toulouse 3, 1995. http://www.theses.fr/1995TOU30214.
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Les leucemies aigues myeloides representent l'expansion clonale de cellules leucemiques bloquees a un stade donne de la differenciation granulo-monocytaire. Malgre son uniformite apparente, le clone leucemique est organise sur un mode similaire a celui de l'hematopoiese normale avec un compartiment de cellules souches (de phenotype precoce) alimentant le compartiment plus mature des blastes en division terminale, qui constituent la vaste majorite des cellules leucemiques observees dans le sang et la moelle des patients. Les protocoles actuels de chimiotherapie font couramment appel a la daunorubicine et a la mitoxantrone. Si ces protocoles sont relativement cytotoxiques sur le compartiment des blastes en division terminale, comme en atteste le taux eleve de reponse, ils sont globalement inefficaces pour eradiquer le compartiment des cellules souches, comme en atteste le fort taux de rechutes. Cette observation clinique suggere l'existence, dans les cellules leucemiques de phenotype precoce, de mecanismes de resistance naturelle a ces agents cytotoxiques. Ce travail, base sur l'utilisation de lignees cellulaires derivees de stades divers de la differenciation granulo-monocytaire, s'attachera a caracteriser les mecanismes de resistance naturelle a la daunorubicine et a la mitoxantrone dans des cellules leucemiques de phenotype precoce. Au travers de quatre travaux experimentaux, nous montrerons que: l'expression d'une p-glycoproteine hyperfonctionnelle joue un role important dans la protection de ces cellules vis a vis de la daunorubicine. La p-glycoproteine est une proteine transmembranaire jouant un role de pompe et assurant l'efflux actif des agents toxiques hors de la cellule. Des cytokines intervenant dans la differenciation granulo-monocytaire peuvent modifier l'expression et/ou la fonction de cette proteine. La distribution intracellulaire de la daunorubicine et de la mitoxantrone est modifiee dans les cellules de phenotype precoce, qu'il s'agisse de lignees cellulaires ou de cellules fraiches de patients. L'apoptose induite par ces deux agents est regulee negativement dans les cellules myeloides leucemiques de phenotype precoce
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Maestre, Nicolas. "Implication des phospholipides à choline dans la réponse des cellules leucémiques aux agents antitumoraux(daunorubicine, taxotère et aracytine)." Toulouse 3, 2001. http://www.theses.fr/2001TOU30041.
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Benzineb, Koulder. "Activation par radiolyse pulsée et gamma d'un médicament antitumoral, la daunorubicine, en présence de peptides et de protéines." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb376118361.
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BENZINEB, KOUIDER, and Christiane Bonnelle. "Activation par radiolyse pulsee et par radiolyse gamma d'un medicament antitumoral : la daunorubicine, en presence de peptides et de proteines." Paris 6, 1988. http://www.theses.fr/1988PA066071.
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Rojas, Amadó Marta. "Efectes de fàrmacs intercalants del DNA en l'Expressió Gènica a "Saccharomyces cerevisiae"." Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/1007.
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S'han estudiat els efectes de dos fàrmacs intercalants al DNA, Daunorubicina (usat com antitumoral) i Criptolepina (amb elevada citotoxicitat i usat com antimalàric), en el llevat "S.cerevisiae".Ambdues molècules s'uneixen al DNA però amb diferent preferència de seqüència: mentre que la Daunorubicina reconeix preferentment regions 5'(A/T)CG3', la Criptolepina s'uneix a 5'GG3'. S'han descrit nombroses regions reguladores riques en aquest tipu de seqüències, pel que ambdós fàrmacs podrien competir amb factors de transcripció nuclears, modificant l'expressió gènica.
Els principals objectius del nostre estudi foren:
1.Determinar l'efecte citotòxic dels dos fàrmacs en diferents soques de S.cerevisiae: BY4741, BY4741-delta-erg6 (soca amb major permeabilitat de la membrana plasmàtica als fàrmacs), BY4741-delta-rad52 (soca amb un gen de la maquinària de reparació delecionat):
- En primer lloc, s'analitzaren els efectes sobre el creixement cel·lular de les soques tractades amb diferents concentracions de cada molècula, tant amb glucosa com galactosa com a fonts de carboni. Els nostres resultats. Els nostres resultats demostren que la permeabilitat de la membrana és necessària per aconseguir la concentració de Daunorubicina que desencadena el seu efecte citotòxic. En canvi, la maquinària de reparació del dany al DNA pot ser una diana potencial de la Criptolepina.
- Mitjançant una anàlisi semiquantitativa de l'expressió d'alguns dels principals gens del metabolisme de la galactosa, es va observar un efecte diferencial dels fàrmacs, ja que el factor regulador dels gens de la galactosa presenta en la seva seqüència consens, la diana per a la Daunorubicina i no per a la Criptolepina. Aquest solapament de seqüència explica el patró repressor induït per la Daunorubicina, però no per a la Criptolepina, resultat que està d'acord amb el major efecte citotòxic de la Daunorubicina en cèl·lules crescudes en galactosa.
2.Avaluar la resposta transcripcional a nivell global de cada intercalant en la soca BY4741-delta-erg6, utilitzant la glucosa com a font de carboni.
- Mitjançant l'ús de microarrays, es va identificar els perfils d'expressió gènica diferencial per a cadascun dels tractaments (Daunorubicina o Criptolepina), en funció de la concentració i del temps. A partir d'aquests experiments es va confirmar que l'efecte de la Daunorubicina sobre la transcripció és pronunciat, mentre que els canvis observats per a la criptolepina són lleus.
- A partir dels resultats obtinguts, es van classificar els gens en diferents categories funcionals i es varen validar els resultats obtinguts per RT-PCR a temps real. Es va observar que tot i que la Daunorubicina reprimeix l'expressió dels gens glicolítics, la criptolepina està associada principalment a la inducció dels gens de resposta a estrès. D'una manera menys significativa, la Criptolepina altera també la transcripció de gens implicats en el transport del ferro i de gens mitocondrials.
- Mitjançant un estudi in silico, es va confirmar que les variacions en els perfils d'expressió gènica es deuen a un efecte directe dels fàrmacs sobre els factors de transcripció que regulen aquests gens, degut a que competeixen per les mateixes dianes d'unió al DNA.
A partir de la identificació dels mecanismes d'acció de cada fàrmac en S.cerevisiae, els nostres resultats plantegen noves vies en el disseny de nous fàrmacs antitumorals i antiparasitaris.
The main objective of this thesis is to analyse the effects of two DNA interacting drugs, Daunorubicin (used as antitumoral) and Cryptolepine (with elevated cytotoxicity and used as an antimalarian) in Saccharomyces cerevisiae. Both drugs intercalate in CG rich regions, the preferent sequence for Daunorubicin being 5'(A/T)CG3' and for Cryptolepine being 5'GG3'. These sites are common in consensus sequences of transcription factors and the competition of drugs for those sites can alter gene expresion.
First, we evaluated the effects in cellular proliferation in yeast strains of different genetic backgrounds (related to membrane permeability and DNA lesion repair), in glucose and galactose as carbon source. We observed that permeability of plasma membrane is necessary in order to reach a citotoxic concentration of Daunorubicin. On the other hand, the DNA repair machinery seems to be a potential target of Cryptolepine.
By a semiquantitative analysis of expression of GAL genes, we observed a differential effect of both drugs. Daunorubicin caused a decrease in GAL genes expression while Cryptolepine did not. This can be due to the fact that the main regulatory protein of galactose metabolism has the preferent binding site for Daunorubicin in the consensus sequences.
The effect of Daunorubicin and Cryptolepine on yeast transcriptome was studied in the most permeable yeast strain using glucose as carbon source. Using microarrays, we identified different gene expression patterns for each drug. Genome wide results were grouped into functional categories and confirmed by real time RT-PCR. We observed that Daunorubicin downregulates glycolytic genes and Cryptolepine induces a stress response and decreases the transcriptional levels of specific genes related to iron transport (siderophores) and mitochondrial genes.
We used in silico assays to correlate the expression patterns induced by both drugs with a direct effect in the regulatory proteins involved in the transcription of these genes. Results confirm different action mechanisms for each intercalating drug tested. Daunorubicin may alter the regulatory complex Gcr1p-Gcr2p responsible of upregulation of glycolytic genes, and Cryptolepine may induce a pleiotropic effect.
Overall, these results can raise new approaches in the development of new antitumour and antiparasit drugs.
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Mas, Véronique de. "Role des seconds messagers lipidiques dans la reponse des cellules de leucemies aigues myeloides a la daunorubicine : implication potentielle dans la resistance des progeniteurs leucemiques." Toulouse 3, 1998. http://www.theses.fr/1998TOU30208.
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L'observation clinique suggere que, dans les leucemies aigues myeloides, les progeniteurs leucemiques sont plus resistants au traitement (daunorubicine (dnr)/cytosine arabinoside (ara-c) que les blastes en division terminale. A partir de lignees leucemiques representatives de la differenciation myeloide, nous avons confirme cette observation et montre que la resistance naturelle a la dnr pouvait etre liee a une regulation negative de l'apoptose. Pour comprendre les mecanismes de resistance impliques dans les cellules immatures, nous avons caracterise, dans les cellules matures (sensibles) u937, les signaux apoptotiques actives par la dnr. Les voies de signalisation mises en evidence dans les cellules matures sont les suivantes : - une voie proapoptotique initiee par l'activation d'une sphingomyelinase neutre (smase) responsable de l'hydrolyse de la sphingomyeline et de la generation de ceramide qui active jnk, une map kinase. L'activation de la smase est regulee par des serine-proteases, l'activite pkc et la production de radicaux oxygenes. - des voies antiapoptotiques initiees par l'activation d'une phosphatidylcholine-phospholipase c (pc-plc) et d'une phosphatidylinositol-3 kinase (pi3k) responsables de la generation de diacylglycerol et de phosphatidylinositol-3,4,5 tris phosphate respectivement. Ces deux voies activent erk, une autre map kinase. Sur la base de nos travaux, la resistance des cellules immatures a la dnr apparait pouvoir etre liee a une modification de la regulation de ces voies de signalisation en faveur de la survie cellulaire : alterations des processus de proteolyse, statut particulier de la pkc, de la pi3k et/ou de la balance oxydative. La validation de ces hypotheses ouvrirait de larges perspectives dans la manipulation pharmacologique dans le but d'ameliorer la cytotoxicite des agents antileucemiques.
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Udomtanakonchai-Loetchutinat, Chatchanok. "Résistance multiple aux antitumoraux : quantification de l'accumulation de sondes fluorescentes dans différents compartiments intracellulaires par combinaison de la spectrofluorescence conventionnelle et de la cytomètrie en flux." Paris 6, 2001. http://www.theses.fr/2001PA066486.
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Dessinges, Aimée. "Synthèse d'hydrates de carbone fluorés et applications biologiques (médecine nucléaire, antibiotiques, inhibiteurs d'enzymes) : les isotopes de l'oxygène en chimie des substances naturelles." Paris 11, 1986. http://www.theses.fr/1986PA112018.
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Cette thèse comporte quatre chapitres distincts. Le premier chapitre traite d'une nouvelle synthèse stéréospécifique du 2-déoxy-2-fluoro-D-glucose et des modifications appropriées 18 à la préparation de son anal gue radioactif, le 2-déoxy-2-[18F] fluoro-D-glucose, utilisé en médecine nucléaire. Dans le deuxième chapitre est rapportée la synthèse de composés fluorés apparentés à l'antibiotique antitumoral, la daunorubicine. Le troisième chapitre traite de la préparation stéréospécifique d'hydrates de carbone dont le carbone-2 est quaternaire et porte les fonctions nitrile et amine ; ceci dans le but de synthétiser les dérivés ᾳ-fluorométhylés et ᾳ-difluorométhylés de la lysine. Le quatrième chapitre est relatif à l'utilisation de la RMN de l’oxygène-17, ainsi qu'à l'observation des déplacements chimiques isotopiques induits par l'oxygène-18 en RMN du 13C ; un mécanisme réactionnel et un chemin biosynthétique ont pu être élucidés à l'aide de ces techniques.
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Stierlé, Vérène. "Reversion du phénotype de résistance multiple aux antitumoraux par les petits ARNs interférents." Paris 6, 2005. http://www.theses.fr/2005PA066612.
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Boulanger, Mathias. "SUMOylation et contrôle de l’expression des gènes : implication dans la réponse à la chimiothérapie d’induction des Leucémies Aigües Myéloïdes." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT067.
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Les Leucémies Aigues Myéloïdes (LAM) sont des hémopathies malignes au pronostic sombre. Leur traitement repose sur une chimiothérapie composée d’une anthracycline (daunorubicine [DNR] ou idarubicine) et d’un analogue de nucléotide (AraC). Cependant, les taux de rechutes sont très élevés. Il est donc critique de mieux comprendre les mécanismes d’actions de ces drogues chimiothérapeutiques pour mieux surmonter la chimiorésistance. Un aspect, essentiel à leur action thérapeutique mais encore mal connu, concerne leur capacité à réguler l’expression de gènes spécifiques qui participent à leur effet thérapeutique. Ma thèse a pour objectif de déterminer l’implication de la SUMOylation, une modification post-traductionnelle de la famille de l’ubiquitine, dans la reprogrammation transcriptionnelle induite par les chimiothérapies dans les LAM. La combinaison d’approches génomiques (ChIP-Seq), de transcriptomiques et de protéomiques a montré que la DNR induit une reprogrammation transcriptionnelle importante et rapide de gènes impliqués dans la régulation de l’inflammation et l’apoptose, précédée par une désumoylation massive des protéines présentes sur les promoteurs des gènes dans les LAM. En particulier, j’ai montré que la diminution de CTCF et de SUMO sur le promoteur du gène NFkB2 régulent son induction transcriptionnelle par la DNR, en particulier en favorisant un changement de la structure 3D de son locusAcute Myeloid Leukemias (AML) are severe hematological malignancies. Their treatment is based on an intensive chemotherapy composed of one anthracycline (daunorubicin-DNR or Idarubicin) and a nucleotide analog (Ara-C). However, the relapse rates are very high and the prognosis bad. It is therefore critical to better understand their modes of action to overcome chemoresistance. One aspect, essential to their action but still poorly understood, concerns their ability to regulate the expression of specific genes, which participate in their therapeutic potential. The objective of my thesis was to determine the role of SUMOylation, a post-translational modifier of the ubiquitin family, in the DNR-induced transcriptional reprogramming in AML. Genomic approaches (ChIP-seq) were combined with transcriptomics and quantitative proteomic to show that DNR induces a fast and large transcriptomic reprogramming of genes involved in apoptosis and inflammation regulation, which is preceded by promoter-bound protein deSUMOylation. In particular, I could show that the decreased binding of CTCF and SUMO on the promoter of NFkB2 regulates its DNR-induced expression through a remodeling of the 3D structure of its locus
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Wilhelm, Matthieu. "Aspects mécanistiques et énergétiques des interactions entre l'ADN et une molécule intercalante." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10108/document.
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L'ADN est au cœur de nombreux processus biologiques. De ce fait, il est la cible de nombreuses molécules pharmacologiques employées notamment dans les thérapies anticancer. Parmi celles-ci, la daunomycine va interagir avec la double hélice d'ADN en s'intercalant entre deux paires de bases, bloquant ainsi la réplication. Malgré l'efficacité reconnue des molécules intercalantes, et de nombreuses études à ce sujet, le mécanisme du processus d'intercalation n'est pas clairement déterminé à l'heure actuelle. Basés sur l'utilisation de la dynamique moléculaire avec une représentation tout atome des systèmes en conditions de solvant explicite, ces travaux ont tout d'abord visé à caractériser l'influence de la flexibilité conformationnelle de la daunomycine vis à vis de l'ADN, ainsi que son importance dans les interactions entre ces deux molécules. Dans un deuxième temps nous nous sommes focalisés sur le chemin réactionnel menant la daunomycine à son site d'intercalation par umbrella sampling. Cette étude, en plus de fournir des énergies libres en accord avec les données expérimentales, a permis de pointer du doigt un mécanisme d'intercalation impliquant une étape préliminaire de liaison de la daunomycine au petit sillon de l'ADN, suivie d'une étape intermédiaire de réorientation du ligand. Finalement, la réalisation de simulations de glissement de la daunomycine le long du petit sillon de l'ADN nous a permis de nous intéresser au mécanisme permettant à ce ligand de localiser son site d'intercalation le long de l'ADNDNA is at the heart of many biological processes. Therefore, it is the target of numerous pharmacological molecules used in cancer therapies. Among them, daunomycin will interact with the double helix by intercalation between DNA’s base pairs, thus blocking replication. Despite the proven efficiency of intercalating molecules, and many studies on this subject, the mechanism of intercalation process is not yet clearly understood. Based on molecular dynamics with an all atoms representation in explicit solvent conditions, this work, in one hand, aim to characterize the influence of the conformational flexibility of daunomycin during interactions with DNA. In a second hand, we focused on the reaction pathway leading daunomycine to its intercalation site using umbrella sampling. This study, in addition to providing free energies in agreement with experimental data, has allowed to highlight an intercalation mechanism involving a preliminary step where daunomycin bind to the minor groove of DNA, followed by a intermediate step of reorientation of the ligand. Finally, the realization of sliding simulations of daunomycin along DNA minor groove, has allowed us to focus on the mechanism that allow a ligand to locate its intercalation site on DNA
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"Daunorubicin kinetics and drug resistance in leukaemia." Thesis, University of Technology, Sydney. Faculty of Science, 1996. http://hdl.handle.net/10453/20146.
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University of Technology, Sydney. Faculty of Science.The aims of this thesis were to examine: (1) plasma and cellular pharmacokinetics of daunorubicin and its major metabolite daunorubicinol in patients with acute leukaemia, and the relationships between pharmacokinetics, patient response and the presence of P glycoprotein; (2) actions of the multidrug resistance reversing agents cyclosporin A and trifluoperazine, at clinically achievable concentrations, on daunorubicin accumulation and retention in human leukaemia cell lines and patients with acute leukaemia; and (3) effect of daunorubicin on the cell membrane of both sensitive and resistant cell lines, with and without the multidrug resistance reversing agents. Twenty-seven patients with acute leukaemia received daunorubicin as part of induction therapy. The plasma and cellular levels of daunorubicin and its metabolite daunorubicinol were determined using HPLC. There were no significant differences between patients who went into complete remission (12 out of 23) compared to those who did not respond for any of the plasma pharmacokinetic parameters. There was a significant difference in the cellular daunorubicin and daunorubicinol area under the concentration-time curve between responders and non responders (p less than 0.02), as well as in cellular Cmax, cellular clearance and cellular volume of distribution. Eleven patients were P glycoprotein positive and 10 P glycoprotein negative (no sample available for 2 patients). There was no correlation between patient response and the presence of P glycoprotein; nor a correlation between the cellular concentration of daunorubicin or daunorubicinol and P glycoprotein. Patients responding to chemotherapy had higher cellular daunorubicin and daunorubicinol compared to non responders. In contrast to in vitro studies, overexpression of P glycoprotein was not the reason for the lower cellular daunorubicin levels. Cyclosporin A was capable of increasing both cellular accumulation and retention in the drug resistant CEM/VLB and HL 60/ADR cell lines, but not in the drug sensitive CEM and HL 60 cell lines. Trifluoperazine had no effect in any of the four cell lines. In contrast to the cell line findings, only the combination of cyclosporin A and trifluoperazine were able to increase both accumulation and retention in the blast cells of patients at initial presentation. The multidrug resistant reversing agents alone had no effect in increasing accumulation or retention in the blast cells of P glycoprotein positive patients, nor patients in relapse. The cell line studies show that at clinically relevant concentrations only cyclosporin A is capable of increasing daunorubicin accumulation in both the drug resistant P glycoprotein positive (VLB) and P glycoprotein negative (ADR) cell lines. Thus, cyclosporin A does not work only by inhibiting the actions of P glycoprotein. Trifluoperazine was unable to reverse drug resistance at clinically relevant concentrations in either cell lines or patient blast cells. However, the combination of cyclosporin A and trifluoperazine increased accumulation in patient blast cells at initial presentation, suggesting that these agents may be more useful in patients at initial presentation than relapse. Daunorubicin was immobilised by linking it to poly vinyl alcohol and the effect of immobilised-daunorubicin was studied on the four cell lines above. The immobilised-daunorubicin was able to decrease cell growth in the drug sensitive HL 60 cell line but not in the drug resistant VLB or ADR cell lines. Poly vinyl alcohol itself was cytotoxic to the CEM cell line. The multidrug resistance reversing agents cyclosporin A and trifluoperazine were only capable of increasing cytotoxicity in the HL 60 cell line, with no effect in the drug resistant VLB or ADR cell lines.
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"Daunorubicin Kinetics and Drug Resistance in Leukaemia." University of Technology, Sydney. Faculty of Science, 1996. http://hdl.handle.net/2100/247.
Full textAbstract:
The aims of this thesis were to examine: (1) plasma and cellular pharmacokinetics of daunorubicin and its major metabolite daunorubicinol in patients with acute leukaemia, and the relationships between pharmacokinetics, patient response and the presence of P glycoprotein; (2) actions of the multidrug resistance reversing agents cyclosporin A and trifluoperazine, at clinically achievable concentrations, on daunorubicin accumulation and retention in human leukaemia cell lines and patients with acute leukaemia; and (3) effect of daunorubicin on the cell membrane of both sensitive and resistant cell lines, with and without the multidrug resistance reversing agents. Twenty-seven patients with acute leukaemia received daunorubicin as part of induction therapy. The plasma and cellular levels of daunorubicin and its metabolite daunorubicinol were determined using HPLC. There were no significant differences between patients who went into complete remission (12 out of 23) compared to those who did not respond for any of the plasma pharmacokinetic parameters. There was a significant difference in the cellular daunorubicin and daunorubicinol area under the concentration-time curve between responders and non responders (p less than 0.02), as well as in cellular Cmax, cellular clearance and cellular volume of distribution. Eleven patients were P glycoprotein positive and 10 P glycoprotein negative (no sample available for 2 patients). There was no correlation between patient response and the presence of P glycoprotein; nor a correlation between the cellular concentration of daunorubicin or daunorubicinol and P glycoprotein. Patients responding to chemotherapy had higher cellular daunorubicin and daunorubicinol compared to non responders. In contrast to in vitro studies, overexpression of P glycoprotein was not the reason for the lower cellular daunorubicin levels. Cyclosporin A was capable of increasing both cellular accumulation and retention in the drug resistant CEM/VLB and HL 60/ADR cell lines, but not in the drug sensitive CEM and HL 60 cell lines. Trifluoperazine had no effect in any of the four cell lines. In contrast to the cell line findings, only the combination of cyclosporin A and trifluoperazine were able to increase both accumulation and retention in the blast cells of patients at initial presentation. The multidrug resistant reversing agents alone had no effect in increasing accumulation or retention in the blast cells of P glycoprotein positive patients, nor patients in relapse. The cell line studies show that at clinically relevant concentrations only cyclosporin A is capable of increasing daunorubicin accumulation in both the drug resistant P glycoprotein positive (VLB) and P glycoprotein negative (ADR) cell lines. Thus, cyclosporin A does not work only by inhibiting the actions of P glycoprotein. Trifluoperazine was unable to reverse drug resistance at clinically relevant concentrations in either cell lines or patient blast cells. However, the combination of cyclosporin A and trifluoperazine increased accumulation in patient blast cells at initial presentation, suggesting that these agents may be more useful in patients at initial presentation than relapse. Daunorubicin was immobilised by linking it to poly vinyl alcohol and the effect of immobilised-daunorubicin was studied on the four cell lines above. The immobilised-daunorubicin was able to decrease cell growth in the drug sensitive HL 60 cell line but not in the drug resistant VLB or ADR cell lines. Poly vinyl alcohol itself was cytotoxic to the CEM cell line. The multidrug resistance reversing agents cyclosporin A and trifluoperazine were only capable of increasing cytotoxicity in the HL 60 cell line, with no effect in the drug resistant VLB or ADR cell lines.
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Yen-Chun, Peng, and 彭彥鈞. "The Molecular Mechanism of Daunorubicin on the Inhibition of Hepatocellular Growth." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/77295182605923492284.
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碩士中國醫藥學院
醫學研究所
91
Abstract Daunorubicin (DNR), an inhibitor of DNA topoisomerase II, was considered as the treatment of choice for hepatocellular carcinoma. Recent studies found that the therapeutic effect of DNR might be through mitogen-activated protein kinase pathway, apoptosis, and cell cycle arrest; however, the molecular basis of DNR on hepatocellular transformation is still unclear. To evaluate the anti-tumor mechanism of DNR on hepatocytes, we examined the effects of DNR on hepatocellular transformation by anchorage-independent transformation assay. Treatment of 0.01 μM DNR for 21 days inhibited colony formation, suggesting that DNR was able to suppress the hepatocellular transformation. Flow cytometry was further used to evaluate the effect of DNR on cell cycle distribution, and reporter assay was employed to examine the effect of DNR on activator protein 1 (AP-1) activity. The data showed that incubation of Chang liver and HepG2 cells with 0.01 μM DNR for 24 h resulted in the accumulation in G2/M phase but not the induction of apoptosis and AP-1 activity. However, the number of apoptotic cells would be slightly induced and AP-1 activity would be down-regulated by the treatment of 1 μM DNR for 24 h and 16 h, respectively. Therefore, the anti-hepatocellular transformation of DNR might be mediated by cell cycle arrest at G2/M checkpoint.
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Chung-Ta, CHANG, and 張仲達. "Study on the Molecular Mechanism of Interaction Between Flavonoids and Daunorubicin." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/25556402962729369290.
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碩士中國醫藥學院
醫學研究所
91
Abstract Primary hepatocellular carcinoma (HCC) is one of the most common tumors in the world. It is especially prevalent in Taiwan, where the annual incidence is up to 28.71 cases per 100,000 population. The most important reason for the high incidence of HCC is the frequency of chronic infection with hepatitis B virus and hepatitis C virus. In addition, alcohol abuse contributes to the development of HCC. There are many therapeutic strategies for the treatment of HCC. For patients who combined with liver cirrhosis or extra-hepatic metastasis, transarterial chemoembolization and chemotherapy are the important treatment applications in clinic. Daunorubicin is an effective anti-cancer drug, which has been used for treating a wide variety of cancers, such as breast and esophageal carcinomas, osteosarcoma, Kaposi’s sarcoma, soft-tissue sarcomas, hepatocellular carcinoma, and Hodgkin’s and non-Hodgkin’s lymphomas. Topoisomerase II is likely to be the major target of daunorubicin. Daunorubicin also inhibits DNA synthesis, DNA strand unwinding, and helicase activity. All of these mechanisms contribute to the G2-M arrest in various cells. Flavonoids are a class of benzo-gamma-pyrone derivatives, which are ubiquitous in vegetables, fruits, grains, and beverages. Previous studies indicate that they have great potentialities in the anti-inflammation, anti-oxidation, anti-virus infection, anti-allergy, and anti-cancer cell proliferation. Some of them also alter intra-cellular metabolism or change the transportation behavior of cell membrane to enhance the effect of anti-cancer drugs. In order to study the interaction between flavonoids and daunorubicin, we used different hepatic cell lines to represent the different clinical stages of HCC. After the addition of different agents into these cells, the cell distribution was analyzed by flow cytometer. The results revealed that apigenin, a member of flavone, arrested the cells in the G2-M phase in a dose-dependent manner. Apigenin also worked with daunorubicin, resulting in the increase of the cell distribution in G2-M phase. In conclusion, our results suggested that apigenin exhibited the synergic effect with daunorubicin in Chang liver/AP-1 cells to enhance the daunorubicin-induced cell growth inhibition, G2-M arrest, and apoptosis.
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Andreev, Emil. "The human organic cation transporter OCT1 mediates high affinity uptake of the anticancer drug daunorubicin." Thèse, 2016. http://hdl.handle.net/1866/16273.
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Les anthracyclines tels que la doxorubicin et la daunorubicin sont une famille de médicaments anticancéreux hydrophiles qui doivent être transportés dans les cellules afin d’exercer leur action par intercalation à l’ADN dans le noyau cellulaire. Ceci mène à la perturbation du métabolisme de l’ADN et entraine la mort cellulaire. Les anthracyclines sont utilisés pour le traitement d’une variété de cancers incluant la leucémie, les lymphomes, le cancer du sein, le cancer des poumons et le cancer des ovaires. Étant donné que le transport actif des anthracyclines dans les cellules a partiellement été démontré, le transporteur spécifique impliqué dans ce processus n’est pas encore connu. En utilisant un modèle de cancer des ovaires, la lignée cellulaire TOV2223G, nous avons démontré que des substrats spécifiques au transporteur de cations organiques 1 (OCT1), notamment la ergothionéine, la thiamine et la phenformin, ont partiellement inhibé l’absorption de la daunorubicin en différence de la carnitine qui est un substrat de haute affinité des transporteurs CT2 et OCTN2. Ces résultats suggèrent que les transporteurs organiques spécifiques au transport de la carnitine ne sont pas impliqués dans le transport des anthracyclines. Ainsi, nos résultats ont démontré que l’absorption de la daunorubicin est orchestrée par le transporteur OCT1 dans les cellules TOV2223G (Km ~ 5 μM) et des concentrations micromolaires de choline ont complètement abolies l’absorption de la drogue. De plus, un ARN sh dirigé contre OCT1 a réprimé son expression protéique, ce qui a été confirmé par la technique d’immuno-buvardage en utilisant un anti-OCT1 anticorps. Les cellules déficientes en OCT1 n’ont pas été capables d’absorber la daunorubicin et ont été plus résistantes à l’action de la drogue par rapport aux cellules contrôle. La transfection des cellules HEK293T avec un plasmide construit de façon à faire exprimer OCT1 comme protéine de fusion avec la protéine fluorescente EYFP a montré que celle-ci est localisée dans la membrane plasmique. Les cellules transfectées ont été capables d’absorber cinq fois plus de daunorubicin comparé aux cellules contrôles. Cette étude est, selon nous, la première à démontrer que OCT1 est un transporteur de haute affinité des anthracyclines. Ainsi, nous avons émis l’hypothèse que des défauts de OCT1 peuvent contribuer à l’efficacité de la réponse des cellules cancéreuses à la chimiothérapie avec les anthracyclines.Anthracyclines such as doxorubicin and daunorubicin are hydrophilic anticancer agents that must be transported into cells. These drugs accumulate in the nucleus where they intercalate with DNA, thereby interfering with DNA replication in turn leading to cell death. Anthracyclines are used for treating a variety of cancers including leukemia, lymphomas, breast, lung, and ovarian. Despite evidence for active uptake of anthracyclines, the specific transporter has not been identified. Using the ovarian cancer cell line TOV2223G, we show that substrates reported for the organic cation transporter OCT1, such as ergothioneine, thiamine and phenformin, partially compete with uptake of daunorubicin, but not of L-carnitine, i.e., a high affinity substrate transported by hCT2 and OCTN2. These findings exclude the involvement of the L-carnitine organic cation family of transporters in anthracycline uptake. Moreover, we show that OCT1 actively mediates high affinity (Km ~ 5 μM) transport of daunorubicin into TOV2223G cells, whereas micromolar amounts of choline completely abolish drug uptake. shRNA-mediated downregulation of OCT1 causes defective uptake of daunorubicin, as well as significant resistance to the drug, as compared to the vector control. Transfection of HEK293T cells with a plasmid expressing OCT1 as a GFP fusion protein revealed that OCT1-EYFP was predominantly localized to the plasma membrane. These transfected cells manifested nearly 5-fold increased uptake of daunorubicin compared to the empty vector control. In summary, we show for the first time that human OCT1 is a high affinity transporter for anthracyclines. As such, we postulate that OCT1 status represents a critical determinant in the response of cancer cells to chemotherapy with anthracyclines
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Bartels, Anna-Maria [Verfasser]. "Durchflußzytometrische Untersuchungen zur zellulären Pharmakokinetik von freien und liposomal verkapseltem Daunorubicin / Anna-Maria Bartels, geb. Hoffmann." 2002. http://d-nb.info/965428001/34.
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Sandkötter, Julia [Verfasser]. "In-vitro-Toxizität der Anthrazykline Daunorubicin und Doxorubicin auf vier verschiedenen Ewing-Sarkom-Zelllinien / vorgelegt von Julia Sandkötter." 2008. http://d-nb.info/991567463/34.
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伊藤, 裕美. "Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin." Thesis, 2011. http://hdl.handle.net/2237/14839.
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Lakomá, Petra. "Vliv alisertibu a brigatinibu na aktivitu vybraných lidských karbonylredukujících enzymů." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-411828.
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Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Petra Lakomá Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: The effect of alisertib and brigatinib on the activity of selected human carbonyl reducing enzymes Key words: brigatinib, alisertib, daunorubicin, inhibition, carbonyl-reducing enzymes Protein kinases are enzymes, whose main function is based on a transfer of phosphate group from ATP to protein substrate. This common posttranslational modification is involved in the regulation of intracellular processes and cell signaling. Altered expression of protein kinases is often coupled with a development of cancer. Inhibition of protein kinases may prevent cancer cell proliferation and induce their cell death. The main aim of the diploma thesis was to measure inhibition potential of protein kinase inhibitors, alisertib and brigatinib, against carbonyl-reducing enzymes. Overexpression of carbonyl-reducing enzymes in cancer cells may cause resistance to drugs followed by failure of chemotherapeutic therapy. In case of antracyclin chemotherapeutic daunorubicin, carbonyl-reducing enzymes reduce the carbonyl in C-13 giving rise a primary metabolite daunorubicinol, which has lower cytotoxic effect but higher cardiotoxicity. The effort to...
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Homerová, Andrea. "Interakce přírodních látek s lidskou aldo-ketoreduktasou 7A2 a dalšími významnými karbonylredukujícími enzymy." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-396873.
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Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Andrea Homerová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Interaction of natural substances with human aldo-keto reductase 7A2 and other important carbonyl reducing enzymes Reduction of carbonyl group is one of the phase I metabolism reactions, which is responsible for production of more polar metabolites, enables conjugation in process of biotransformation, excretion of the molecule and it also causes decrease in reactivity and biological activity of the molecule. Endogenous as well as exogenous compounds undergo this reaction and carbonyl reducing enzymes are the ones which possess this reducing activity. Based on the structure, we can divide the enzymes into several groups: short-chain dehydrogenases/reductases, medium-chain dehydrogenases/reductases, aldo-keto reductases and quinone reductases. Inhibition of carbonyl reducing enzymes appears to be a promising aim of research. It is important to take into consideration that by inhibiting carbonyl reducing enzymes it is possible to reduce production of less active, but more toxic metabolites, for example in anthracycline chemoteraputics daunorubicin and doxorubicin and that can lead to change in therapy of cancer. This study...
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Tomanová, Alžbeta. "Vliv vybraných inhibitorů tyrosinkinas na aktivitu lidských enzymů redukujících karbonylovou skupinu." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-404713.
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Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Alžbeta Tomanová Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: Effect of selected tyrosine kinase inhibitors on the activity of human carbonyl reducing enzymes Key words: tyrosin kinases, screening, carbonyl, daunorubicin, inhibition Tyrosine kinases are a subclass of protein kinases, catalysing the transfer of ATP phosphate residue to a protein, thereby playing an important role in cellular signaling. Abnormal tyrosine kinase activity is present in various malignancies. In certain cases, inhibition of their function can prevent tumor cell proliferation and eventually induce apoptosis. At the same time, some tyrosine kinase inhibitors have demonstrated the ability to inhibit efflux transporters, which are often involved in the development of resistance to anticancer treatment. In this diploma thesis, the inhibitory effect of imatinib, nilotinib, dasatinib and acalabrutinib (tyrosine kinase inhibitors) has been studied on carbonyl reducing enzymes, whose overexpression by tumor cells may lead to resistance to chemotherapy. In particular, in the case of anthracyclines, the reduction of carbonyl group on C-13 results in not only lower cytotoxic activity, but also increased...
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"Sphingosine kinase 1 expression is involved in leukemogenesis and modulates cellular sphingolipid rheostat, which is a good predictive marker of daunorubicin sensitivity." Thesis, 2008. http://hdl.handle.net/2237/9693.
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祖父江, 沙矢加, and Sayaka SOBUE. "Sphingosine kinase 1 expression is involved in leukemogenesis and modulates cellular sphingolipid rheostat, which is a good predictive marker of daunorubicin sensitivity." Thesis, 2008. http://hdl.handle.net/2237/9693.
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Schröder, Anke [Verfasser]. "In-vitro-Toxizität der liposomal verkapselten Anthrazykline Daunorubicin (Daunoxome) und Doxorubicin (Caelyx) auf vier verschiedenen Ewing-Sarkom-Zelllinien / vorgelegt von Anke Schröder." 2004. http://d-nb.info/971791562/34.
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Adamíková, Klára. "HPLC analýza daunorubicinu a jeho metabolitu." Master's thesis, 2013. http://www.nusl.cz/ntk/nusl-322723.
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At present, the High Performance Liquid Chromatography (HPLC) is still the dominant separation method, it is widely used in all areas of drug analysis. HPLC provides qualitative and quantitative evaluation of the separated components. This thesis describes the development of the method for HPLC analysis of daunorubicin (DAU) and its metabolite daunorubicinol (DAU-OL) in a rabbit plasma. The analyzed compounds were first separated from interfering substances in plasma due the deproteinization. For a precipitation was chosen methanol (600 μl) with the highest extraction efficiency. The separation of DAU and its metabolite was reached by Zorbax SB-Aq column (3,5 µm, 150 x 4,6 mm; Agilent Technologies, USA), the mobile phase consisted of a mixture of water with phosphate butter and phosphoric acid (pH 2,4) and acetonitril (74:26, v/v). The analysis ran at isocratic mode during 15 minutes. The mobile phase was delivered at a rate of 1,1 ml/min, an aliquot of 40 μl was injected into the chromatographic system. The fluorescence detector was operated at an excitation wavelength of 480 nm and an emission wavelength of 560 nm. Doxorubicin was used as an internal standard. The methodology was validated with respect to linearity (4 - 83 ng/ml for DAU, 25 - 500 ng/ml for DAU-OL), precision and accuracy. The...
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Nováková, Mária. "Hodnocení stability daunorubicinu a doxorubicinu pomocí HPLC." Master's thesis, 2017. http://www.nusl.cz/ntk/nusl-356255.
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The purpose of this thesis was to determine the stability of doxorubicin and daunorubicin, both in the form of hydrochloride, in water, in a rabbit application solution (0.9% NaCl solution), and culture medium using HPLC with a fluorescence detector. Doxorubicin and daunorubicin belong to the group of anthracycline antibiotics used in the treatment of various types of cancer. The stability of the substances has been investigated in water and 0.9% NaCl stored in glass and plastic (polypropylene) at room temperature in light and dark for 24 hours, in a refrigerator (8řC) for 3 months, in a freezer (-80řC) for 3 months, and repeatedly frozen (-80řC) and thawed (room temperature), totaling 3 times. The stability of the substances in culture medium has been investigated in glass and plastics (polypropylene) at room temperature in light and dark for 3 days Additionally, stock solutions were stored at 37řC in thermomixers protected from light in plastics (polypropylene) and in an incubator in glass and plastics (polypropylene and polystyrene) and examined for 3 days. They were also examined for their stability at repeated frozen (-80řC) and thawing (room temperature) of undiluted solutions and solutions diluted with 90% methanol.