Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis The Mechanisms Responsible for Nilotinib Resistance in Human Chronic Myeloid Leukemia Cells(Izmir Institute of Technology, 2010) Camgöz, Aylin; Baran, Yusuf; Baran, Yusuf; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyMultidrug resistance remains a significant obstacle to successful chemotherapy. The ability to determine the possible resistance mechanisms and surmount the resistance is likely to improve chemotherapy. Nilotinib is a very effective drug in the treatment of sensitive or Imatinib resistant patients. Although very successful hematologic and cytogenetics responses have been obtained in Nilotinib-treated patients, in recent years resistance cases were observed. The main objective of the project is to understand the mechanisms underlying multidrug resistance to Nilotinib to provide new targets for the treatment of chronic myeloid leukemia (CML). In this study, continuous exposure of cells to step-wise increasing concentrations of Nilotinib resulted in the selection of cells resistant to 50 nM Nilotinib and referred to as K562/NIL-50. Expression analyses of BCR-ABL gene demonstrated BCR-ABL was upregulated in resistant cells as compared to parental sensitive cells. However, nucleotide sequence analyses of ABL kinase gene revealed that there was no mutation in Nilotinib binding region of the gene in resistant cells. There was also an increase in expression levels of MRP1 gene in resistant cells, which transports the toxic substances outside of cells. Besides, Bax, which is one of the apoptosis inducing genes, was dowregulated in resistant cells. In addition to this, in resistant cells, while GCS and SK-1 genes were overexpressed, decrease in expression levels of LASS1 gene was observed. In conclusion, we determined mechanisms involved in Nilotinib resistance in CML in vitro. Targeting this mechanisms, besides inhibition of BCR-ABL may be a good way of treatment of CML.Master Thesis Increasing Chemosensitivity of Chronic Myeloid Leukemia Cells To Dasatinib by Targeting Bioactive Sphingolipids(Izmir Institute of Technology, 2010) Gencer, Emel Başak; Baran, Yusuf; Baran, Yusuf; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologySphingolipids are bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, senescence, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1-phosphate (S1P) and glucosyl ceramide, converted from ceramides by sphingosine kinase-1 (SK1) and glucosyl ceramide synthase (GCS) enzymes respectively, inhibit apoptosis, induce cell proliferation and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) by itself and in combination with dasatinib in addition to investigate the roles of ceramide metabolising genes in dasatinib induced apoptosis. Our results demonstrated that application of ceramide analogs and inhibitors of ceramide clearance enzymes decreased cell proliferation and induced apoptosis. On the other hand, targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib synergistically. It was also shown for the first time by this study that dasatinib induces apoptosis through downregulating expression levels of GCS, and SK-1 genes and upregulating expression levels of LASS1, -2, -4, -5, and -6 in K562 cells. However, in Meg-01 cells, dasatinib downregulates expression levels of apoptotic LASS genes. Increasing endogenous ceramides through exogenous ceramide analogues or mimetics and decreasing prosurvival lipids, S1P and GC, can open the way of more effective treatment of CML.