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Chronic myeloid leukemia is a well known disease. The must targeted treatments are the tyrosine kinas inhibitors. The inhibitory action on the anarchic proliferation of cells seems to be the best method to delay or stop the evolution of disease. The Glivec® is the paradigm in CML treatment. The discovery of this compound has considerably elevated the life level of patients suffering from chronic myeloid leukemia. Other tki showed their effectiveness, including nilotinib and dasatinib. Nevertheless, such patients develop resistance mechanism against tki. The bypass of these resistance mechanisms raises a lot of interest office of scientists La leucémie myéloïde chronique est une maladie relativement bien connue. Les traitements les plus ciblés actuellement sont les inhibiteurs des tyrosines kinases. En effet, l’action inhibitrice sur la prolifération anarchique des cellules s’avère être la méthode la plus efficace pour retarder ou stopper l’évolution de la maladie. Le paradigme du traitement de la LMC est le Glivec®. La découverte de ce médicament a considérablement augmenté le niveau de vie des patients souffrant de leucémie myéloïde chronique. D’autres inhibiteurs de tyrosine kinase (tki) ont montré leur efficacité, c’est le cas par exemple du nilotinib et du dasatinib. Cependant, chez certains patients, on voit apparaître des mécanismes de résistance aux inhibiteurs de tyrosine kinase. Le détournement de ces mécanismes de résistance suscite beaucoup d’intérêt auprès des chercheurs
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Nowadays, many people are affected by different types of cancer, including chronic myeloid leukemia. In 2001, imatinib mesylate, an effective treatment for this pathology, was introduced on the market. This tyrosine kinase inhibitor has proved its effectiveness following the IRIS study. That is why it has been considered the only first-line treatment for a long time. However, over the years, this medication has encountered numerous resistances resulting in loss of hematological, cytogenic or molecular responses in patients. The question that arises is the following: what are the resistance mechanisms to imatinib and what are the solutions? My dissertation focused on several points to answer this question. After analyzing the resistances, the mutations, representing 40 to 60 % of the whole, were discussed. Among them, T315I, F317L and Y253H have been studied in order to discover solutions. Second – and third-generation tyrosine kinase inhibitors are effective. It is from these results that the practitioner chooses the most appropriate treatment but it is not the only element to consider: it is important to take into account the adverse effects. These are binding for patients and therefore a source of non-compliance. Studies on the minimum duration of treatment are under way and could better manage the disadvantages. De nos jours, nombreuses sont les personnes touches par différents types de cancers, notamment la leucémie myéloïde chronique. En 2001, l’imatinib mésylate, traitement efficace de cette pathologie, a été introduit sur le marché. Cet inhibiteur de tyrosine kinase a prouvé son efficacité suite à l’étude IRIS. C’est pourquoi, il a été longtemps considéré comme l’unique traitement de première ligne. Toutefois, avec les années, cette médication a rencontré de nombreuses résistances entraînant des pertes de réponses hématologiques, cytogéniques ou encore moléculaires chez les patients. La question qui en découle est donc la suivante : quelles sont les mécanismes de résistances à l’imatinib ainsi que les solutions y apportés ? Mon mémoire s’est articulé autour de plusieurs points afin de répondre à cette interrogation. Après avoir analysé les différentes résistances, les mutations, représentant 40 à 60 %, de l’ensemble, ont été abordées. Parmi celles-ci, T315I, F317L et Y253H ont été étudiées de manière à découvrir des solutions. Ce sont les inhibiteurs de tyrosine kinase de deuxième et troisième génération qui ont démontré leur efficacité. C’est à partir de ces résultats que le praticien choisira le traitement le plus approprié mais ce n’est pas le seul élément à considérer : il est important de prendre en compte les effets indésirables. Ces derniers sont contraignants pour les patients et donc une source de non-compliance. Des études sur la durée minimale du traitement sont en cours et permettraient de mieux gérer les inconvénients.
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Protein Kinase Inhibitors --- Leukemia, Myelogenous, Chronic, BCR-ABL Positive --- Signal Transduction --- Leukemia, Myeloid, Acute --- therapeutic use --- drug therapy --- pathology
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Molecular Pathogenesis and Treatment of Chronic Myelogenous Leukemia provides a comprehensive understanding of the recent molecular genetics of Chronic Myelogenous Leukemia (CML) and a characterization of the molecular targets for drug development. Included are therapeutic implications, diagnosis, and prognosis for understanding and facilitating daily practice in the management of patients with CML. Understanding of the pathogenesis and therapy of hematological malignancies such as CML has grown significantly in recent years. This development owe much to the progress in molecular biology and now makes a major contribution to diagnosis and to treatment that pharmacologically targets the molecular events of CML. Molecular targeting therapy with newly developed agents such as small molecules and antibodies for hematological malignancies are being discovered after years of research. Some of these, including tyrosine kinase inhibitors such as imatinib, nilotinib, and dasatinib, lead to increased survival rates and improved therapies. With the opinion leaders of basic and clinical research in the field as authors, this book reviews recent advances in the biology of CML.
Chronic myeloid leukemia --- Pathology --- Protein Kinase Inhibitors --- Genetics --- Antineoplastic Agents --- Drug Therapy --- Leukemia, Myelogenous, Chronic, BCR-ABL Positive --- Leukemia, Myeloid --- Medicine --- Therapeutics --- Enzyme Inhibitors --- Therapeutic Uses --- Biology --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Health Occupations --- Molecular Mechanisms of Pharmacological Action --- Biological Science Disciplines --- Pharmacologic Actions --- Leukemia --- Disciplines and Occupations --- Natural Science Disciplines --- Neoplasms by Histologic Type --- Chemical Actions and Uses --- Neoplasms --- Chemicals and Drugs --- Diseases --- Health & Biological Sciences --- Molecular aspects --- Molecular aspects. --- Treatment. --- Leucaemia --- Leucemia --- Leucocythaemia --- Leucocythemia --- Leucosis --- Leukaemia --- Leukosis --- Chronic granulocytic leukemia --- Chronic myelocytic leukemia --- Chronic myelogenous leukemia --- CML (Disease) --- Anemia --- Cancer --- Leucocytosis --- Preleukemia --- Chronic leukemia --- Myeloid leukemia --- Hematology. --- Oncology . --- Oncology. --- Tumors --- Haematology --- Internal medicine --- Blood
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