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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Étude de systèmes moléculaires programmés pour le ciblage thérapeutique d'agents anticancéreux / Study of programmed molecular systems for selective cancer chemotherapy

Legigan, Thibaut 21 November 2012 (has links)
Malgré les efforts extrêmement importants réalisés pour la recherche de nouveaux agents anticancéreux, les traitements par chimiothérapie ne permettent toujours pas de traiter efficacement un grand nombre de tumeurs. En effet, les molécules utilisées cliniquement ne sont généralement pas sélectives des tissus cancéreux et la destruction des tissus sains qu'elles engendrent provoque de lourds effets secondaires. Le développement de nouvelles stratégies thérapeutiques plus sélectives représente donc un intérêt majeur en chimie médicinale. Dans ce cadre, nous avons développé plusieurs vecteurs non toxiques conçus pour reconnaître des spécificités liées à la malignité puis libérer de manière contrôlée des agents cytotoxiques exclusivement au niveau de la tumeur. Dans le cadre de cette thèse, le concept de vecteur glucuronylé a été adapté à la MMAE et à la cyclopamine. Ces vecteurs pourront être sélectivement activé par la B-glucuronidase présente en concentration importante dans les zones nécrotiques de nombreuses tumeurs solides et ainsi libérer ces agents anticancéreux au niveau des tissus cancéreux. Des études préliminaires visant à évaluer l'efficacité de ces composés in-vitro et in-vivo ont montré la validité de cette approche. Dans un deuxième temps, un vecteur glucuronylé de la doxorubicine pouvant se lier à l'albumine plasmatique a été conçu. Une étude réalisée chez la souris a montré que ce composé possède une efficacité thérapeutique similaire à celle de la doxorubicine et ne provoque pas les effets secondaires constatés lors du traitement avec la drogue seule. La troisième partie est consacrée au développement du premier vecteur activable par la B-galactosidase ut / Despite several years of intensive research devoted to the discovery of novel anticancer agents, chemotherapy is still not entirely effective for the treatment of many solid tumors. Most of the drugs used clinically act by anti-proliferative mechanisms and lack any intrinsic selectivity, leading to severe adverse effects due to the destruction of normal tissues. Therefore, the development of more selective therapeutic approaches has become a major goal in medicinal chemistry. Within this framework, we have developed several nontoxic drug carriers designed for both the efficient recognition of malignant specificities and the controlled release of anti-neoplastic agents exclusively at the tumour site. First, we applied the concept of glucuronide prodrugs to MMAE and Cyclopamine in order to deliver these anticancer drugs at the tumor site. Indeed, glucuronide prodrugs can be selectively activated by B-glucuronidase present in high concentration in necrotic area of numerous solid tumors. Preliminary in vitro and in vivo evaluations of these prodrugs demonstrated the potential of this approach. Second, we studied the first B-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. In vivo experiment conducted in mice show that this compound inhibits tumor growth in a similar manner to doxorubicin whilst avoiding side effects induced by the free drug. We also developed the first B-galactosidase-responsive drug delivery system suitable for the treatment of solid tumors in PMT. Such a targeting system can be selectively activated by lysosomal B-galactosidase located inside malignant cells expressing a specific tumor-a
2

Microarranjos de DNA para análise da expressão gênica em cepas de Trypanosoma cruzi suscetíveis e resistentes a benznidazol. / DNA microarray for gene expression analysis of Trypanosoma cruzi strains sensitive and resistant to benznidazole.

Vigo, Margoth Mitchela Moreno 27 November 2008 (has links)
Benznidazol (BZ) é uma das duas drogas usadas no tratamento da doença de Chagas. Falhas terapêuticas são observadas em muitos pacientes, que foram atribuídas, principalmente, às diferenças na suscetibilidade de cepas do Trypanosoma cruzi a essa droga. Alguns genes foram implicados na resistência induzida a BZ, mas não na resistência natural. O objetivo geral deste estudo foi investigar diferenças de expressão gênica em cepas de T. cruzi naturalmente resistentes e suscetíveis a BZ, utilizando microarranjos de DNA. Quantificamos a sensibilidade à droga em cepas de laboratório e isolados obtidos de pacientes crônicos submetidos a quimioterapia com BZ. Concluímos que os valores de CI50 não são preditivos cura. Os experimentos de microarranjos e ensaios de RT-PCR mostram que a abundância de transcritos do gene TcABCG1, foi maior em cepas naturalmente resistentes a BZ. Não observamos variação na abundância de transcritos de alguns genes implicados no fenótipo de resistência induzida. Nossos dados sugerem o envolvimento do transportador TcABCG1 na resistência a BZ. / Benznidazole (BZ) is one of the two drugs used to treat Chagas disease. Therapeutic failures were reported in many chronic patients, which were mostly attributed to different susceptibilities of Trypanosoma cruzi strains to BZ. A few genes have been implicated in the induced resistance to BZ, but none in the natural resistance. The general goal of this study was to investigate differences in gene expression between susceptible and naturally resistant T. cruzi strains employing DNA microarray technology. We have quantified the drug activity for laboratory strains and for isolates retrieved from chronic patients submitted to BZ therapy. Our results indicate that the IC50 values are not predictive of cure. The microarray and RT-PCR experiments showed the higher abundance of transcript of TcABCG1 gene in naturally resistant strains as compared to sensitive strains. We observed no variation in the transcripts levels of the genes implicated in the induced drug resistance. Our data suggest that TcABCG1 transporter may be involved in natural drug resistance in T. cruzi.
3

Microarranjos de DNA para análise da expressão gênica em cepas de Trypanosoma cruzi suscetíveis e resistentes a benznidazol. / DNA microarray for gene expression analysis of Trypanosoma cruzi strains sensitive and resistant to benznidazole.

Margoth Mitchela Moreno Vigo 27 November 2008 (has links)
Benznidazol (BZ) é uma das duas drogas usadas no tratamento da doença de Chagas. Falhas terapêuticas são observadas em muitos pacientes, que foram atribuídas, principalmente, às diferenças na suscetibilidade de cepas do Trypanosoma cruzi a essa droga. Alguns genes foram implicados na resistência induzida a BZ, mas não na resistência natural. O objetivo geral deste estudo foi investigar diferenças de expressão gênica em cepas de T. cruzi naturalmente resistentes e suscetíveis a BZ, utilizando microarranjos de DNA. Quantificamos a sensibilidade à droga em cepas de laboratório e isolados obtidos de pacientes crônicos submetidos a quimioterapia com BZ. Concluímos que os valores de CI50 não são preditivos cura. Os experimentos de microarranjos e ensaios de RT-PCR mostram que a abundância de transcritos do gene TcABCG1, foi maior em cepas naturalmente resistentes a BZ. Não observamos variação na abundância de transcritos de alguns genes implicados no fenótipo de resistência induzida. Nossos dados sugerem o envolvimento do transportador TcABCG1 na resistência a BZ. / Benznidazole (BZ) is one of the two drugs used to treat Chagas disease. Therapeutic failures were reported in many chronic patients, which were mostly attributed to different susceptibilities of Trypanosoma cruzi strains to BZ. A few genes have been implicated in the induced resistance to BZ, but none in the natural resistance. The general goal of this study was to investigate differences in gene expression between susceptible and naturally resistant T. cruzi strains employing DNA microarray technology. We have quantified the drug activity for laboratory strains and for isolates retrieved from chronic patients submitted to BZ therapy. Our results indicate that the IC50 values are not predictive of cure. The microarray and RT-PCR experiments showed the higher abundance of transcript of TcABCG1 gene in naturally resistant strains as compared to sensitive strains. We observed no variation in the transcripts levels of the genes implicated in the induced drug resistance. Our data suggest that TcABCG1 transporter may be involved in natural drug resistance in T. cruzi.

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