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Régulation de la biosynthèse des acides nucléiques : conception et étude d'effecteurs métaboliques / Regulation of nucleic acids biosynthesis : design and study of metabolic effectorsHospital, Audrey 28 November 2013 (has links)
Les analogues de nucléoside représentent une famille d'agents thérapeutiques très largement utilisée en chimiothérapie anticancéreuse. Cependant des phénomènes de résistance d'origine multifactorielle apparaissent chez les patients atteints de leucémie et il semble que la surexpression d'une enzyme, la 5'-nucléotidase cytosolique de type II (cN-II) soit un des facteurs impliqués. Nous nous sommes donc intéressés à la synthèse et à l'étude d'inhibiteurs potentiels de cN-II du type analogues de nucléoside phosphonate. Ce manuscrit rapporte dans un premier temps le contexte biologique des travaux de thèse, et les découvertes ayant supposés l'implication de la cN-II dans les mécanismes de résistance associés à l'utilisation clinique de nucléosides cytotoxiques. Le deuxième chapitre décrit la synthèse d'analogues phosphonates de l'uridine et de la cytosine modifiés en position 5, ainsi que leur évaluation biologique vis-à-vis de la cN-II purifiée. Enfin, la mise au point d'une stratégie inédite, via l'ouverture d'un époxynucléoside par un phosphite, a permis de synthétiser des béta-hydroxyphosphonates en série purique, et également d'obtenir les prodrogues bis(SATE) correspondantes. / Nucleosidic analogs are widely used as therapeutic agents in antitumoral chemotherapy. However, cellular resistance appears in a multifactorial manner in leukemic patient and it seems that the overexpression of a nucleotidase, the 5'-cytosolic nucleotidase (cN-II) is involved in this phenomenon. We focused our interest on the synthesis and the study of potential inhibitors belonging to the family of phosphonate nucleoside analogs. First, we reviewed literature data about the biological context of our research, especially concerning the involvement of cN-II in resistance phenomenon. Then, we described the synthesis of various phosphonate nucleosides bearing 5-modified uracil and cytosine as nucleobase, as well as their evaluation as inhibitors against the purified enzyme. Finally, a novel strategy for the synthesis of beta-hydroxyphosphonate nucleosides in purine series was designed and developed, and then applied to the synthesis of the corresponding bis(SATE) prodrugs.
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Synthèse et étude d'inhibiteurs potentiels de nucléotidases / Synthesis and study of potential inhibitors of nucleotidasesNguyen, Van Tai 24 October 2016 (has links)
Les analogues de nucléosides représentent une famille d’agents thérapeutiques très largement utilisée en chimiothérapie anticancéreuse. Cependant des phénomènes de résistance d’origine multifactorielle apparaissent chez les patients atteints de leucémie et il semble que deux protéines appartenant à la famille des 5’-nucléotidases (la nucléotidase cytosolique de type II, cN-II et l’ectonucléotidase, CD73) puissent être impliquées. Nous nous sommes donc intéressés à la synthèse et à l’étude d’inhibiteurs potentiels de cN-II ou de CD73 du type analogue de nucléosides phosphonates. Ce manuscrit rapporte dans un premier temps le contexte biologique des travaux de thèse, et les découvertes ayant supposées l’implication des protéines cibles dans les mécanismes de résistance. Le deuxième chapitre décrit la synthèse d’une série d’analogues beta-hydroxyphosphonates incluant une nucléobase modifiée de type 1,2,3-triazolo, ainsi que leur évaluation biologique vis-à-vis de la cN-II purifiée. Enfin, des résultats préliminaires ont été obtenus concernant de nouvelles structures capables d’inhiber modestement l’activité enzymatique de CD73. / Nucleosidic analogs are widely used as therapeutic agents in antitumoral chemotherapy. However, cellular resistance appears in a multifactorial manner in leukemic patients and it seems that two proteins belonging to the 5’-nucleotidase family (the 5’-cytosolic nucleotidase, cN-II and the ectonucleotidase, CD73) may be involved in these phenomenon. We focused our interest on the synthesis and the study of potential inhibitors belonging to the family of phosphonate nucleoside analogs. First, we reviewed literature data about the biological context of our research, especially concerning the involvement of these two targeted proteins in resistance phenomenon. Then, we described the synthesis of a series of beta-hydroxyphosphonate nucleosides incorporating 1,2,3-triazolo moiety as nucleobase, as well as their evaluation as inhibitors against the purified enzyme. Finally, preliminary results concerning the design of novel inhibitors of CD73 were reported.
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Multielectrode platform for measuring oxygenation status in multicellular tumor spheroidsSheth, Disha B. 25 April 2011 (has links)
No description available.
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The Role of Stress Proteins in Cellular Resistance to Photodynamic Therapy in Bladder Cancer T24 Cells and Colon Cancer HT29 Cells / The Role of Stress Proteins in Cellular Resistance to Photodynamic TherapyHanlon, John 06 1900 (has links)
As Photodynamic Therapy (PDT) becomes increasingly popular as a treatment modality for some solid tumours, the need for a better understanding of the mechanism(s) of action and resistance are paramount. To this end we have generated Photofrin® PDT-induced resistant variants to numerous cell lines including the colon cancer cell line HT29. There is significant evidence indicating that stress proteins play an important role in determining the outcome of PDT on a cell. In this thesis the roles of the mitochondrial Heat Shock Protein 60 (Hsp60) as well as the endoplasmic Glucose Related Protein 78 (GRP78) were examined in the HT29 cells and their Photofrin induced resistant variant HT29-P14. The expression and role of these two stress proteins were also examined in T24 Bladder carcinoma cells and their GRP 78 stable-overexpressing clones Hsp60 protein was expressed at slightly higher basal levels in the resistant HT29-P14 cells relative to the parental HT29 cells. After incubation alone or PDT action, a temporal and dose dependent induction of Hsp60 was observed and this too was found to be significantly greater in the resistant cells. In the T24 model, no Hsp60 induction was observed following drug incubation or PDT. GRP78 protein levels were increased by PDT action but not by Photofrin® incubation alone in all cell lines tested. In the T24 model, GRP78 transfection resulted in a stable 2-fold increase in protein levels and a 10-20-fold increase in cell survival after PDT at the highest dose tested. A temporal and dose dependent response was noted in all cells and induction of GRP78 protein was lower in the stable overexpresser such that all cell lines had similar post induction levels. In the HT29 and HT29-P14 resistant cells, GRP78 protein levels were similar at basal level, and, both cell lines exhibited the same temporal and dose dependent increases in expression post PDT. Finally, broad scale expression profiling using a "stress" microarray in the HT29 and HT29-P14 resistant variants revealed a very similar expression profile for the 168 of the 169 stress proteins tested with the exception of the small Heat Shock Protein 27 (Hsp27). As confirmed by northern and western blot analysis, Hsp27 is over 20 fold greater at the transcriptional level and 10-15 fold greater at the translational level in the HT29-P14 resistant variant. These findings implicate Hsp27, Hsp60 and GRP78 as possible mediators of cellular sensitivity to Photofrin-mediated PDT. Specifically, Hsp27 appears to play a role in the increased resistance of our induced resistant HT29-P14 cells. / Thesis / Master of Science (MS)
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