Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
Browse
6 results
Search Results
Master Thesis Investigation of Anticancer Properties of Novel Mdm2 Inhibitors(Izmir Institute of Technology, 2021) Özdemir, Sefayi Merve; Çağır, AliCancer is one major disease causing death worldwide. Current cancer treatments are not %100 effective to cure for patients, yet. Thereby, the synthesis and discovery of new therapeutics have been important to improve the survival period of the cancer patients. There are many strategies for synthesis of cancer therapeutics. One of the most important strategy for cancer treatment is the reactivation of p53. MDM2 is a negative regulator of p53 in cell, because it causes the inactivation of p53. In this thesis, the anticancer and MDM2 inhibitory properties of ezetimibe, desfluoro ezetimibe and intermediates during ezetimibe synthesis (named as SM2-9) and a side product from the synthesis of benidipine (named as SM1) on prostate cancer (LnCAP, wild-type p53), breast cancer (MCF7, wild type p53) and uterus cancer (HeLa, wild type nonfunctional p53) cells were investigated. For this purpose, the cytotoxic, cytostatic and apoptotic properties of these compounds were determined. Compounds SM2, SM3, SM4 and SM6 demonstrated cytotoxic effects, whereas compounds SM5, SM8 and SM9 had cytostatic effects on three cells. Compound SM7 had no effect on these cells, up to 100 μM concentration. Compounds SM1 had cytostatic effect on MCF7 cells, but it showed no activity on other cells. Compounds SM8 and SM9 had strong cytostatic activity. Thus, the apoptotic properties of these compounds were examined by caspases 3/7 activation and Annexin-V FITC assays. Besides, MDM2 inhibitor profiles of these compounds were investigated by fluorescence polarization assay. This study provides novel and potential molecules for drug discovery in cancer treatmentMaster Thesis Interactions of Cancer Cells and Macrophages on the Egf-Egfr Axis: Chemotaxis, Haptotaxis or Direct Contact?(Izmir Institute of Technology, 2017) Önal, Sevgi; Pesen Okvur, Devrim; Bulmuş Zareie, Esma VolgaBreast cancer cells (BCC) and macrophages are known to interact via epidermal growth factor (EGF) produced by macrophages and colony stimulating factor-1 (CSF-1) produced by BCC. Despite contradictory findings, this interaction is perceived as a paracrine loop. Yet, the underlying mechanism of interaction remains unclear. Here, we investigated interactions of BCC with macrophages in 2D and 3D. BCC did not show chemotaxis to macrophages in custom designed 3D cell-on-a-chip devices, which was in agreement with ELISA results showing that macrophage-derived-EGF was not secreted into macrophage-conditioned-medium. Live cell imaging of BCC in the presence and absence of iressa showed that macrophages but not macrophage-derivedmatrix modulated adhesion and motility of BCC in 2D. 3D co-culture experiments in matrigel and collagen showed that BCC changed their multicellular organization in the presence of macrophages. In custom designed 3D co-culture cell-on-a-chip devices, macrophages reduced and promoted migration of BCC in matrigel and collagen, respectively. Furthermore, adherent but not suspended BCC endocytosed EGFR when in contact with macrophages. Collectively, our data revealed that macrophages showed chemotaxis towards BCC-derived-CSF-1 whereas BCC required direct contact to interact with macrophage-derived-EGF. We propose that the interaction between cancer cells and macrophages is a paracrine-juxtacrine loop of CSF-1 and EGF, respectively.Master Thesis Antiproliferative Properties of 2'-alkoxymethyl Substituted Klavuzon Derivatives(Izmir Institute of Technology, 2017) Yıldız, Mehmet Salih; Pesen Okvur, Devrim; Çağır, Ali; Çağır, Ali; Pesen Okvur, DevrimOne of the main objectives of studies on anticancer agents is that the agent is expected to show a high cytotoxic activity on cancer cells and show a less cytotoxic effect on the contrary in healthy cells or never show cytotoxic activity. (R)- goniothalamin, isolated from the Goniothalamus plant, is a styryl lactone and has been found to have a selective antiproliferative property on cancer cells in studies conducted. The Michael acceptor feature in the structure of goniothalamin is thought to be covalently bonded to the nucleophilic side chains of the enzymes and show activity in this way. In previous studies, it has been shown that 1-naphthyl substituted 5,6-dihydro- 2H-pyran-2-one derivatives and 4'-methyl klavuzon derivatives exhibit higher cytotoxic activity on cancer cells than goniothalamin. In this study, antiproliferative properties of newly synthesized 2'-alkoxymethyl substituted klavuzon derivatives have been examined and MIA PaCa-2 pancreatic cancer cell lines and HPDEC pancreatic healthy cell lines were used. MTT cell viability tests were performed at the first step of this study. As a result of this study, it has been observed that the 2'-isobutoxymethylklavuzon derivative has selective cytotoxic activity on the MIA PaCa-2 cell line. It showed activity at lower concentrations than goniothalamin. Cytotoxic activities of the compounds are associated with the size of the R group at position 2’-. Methoxymethyl substituted the worst selective activity among these compounds whereas isobutoxy derivative the best selective one. In the second stage of the study, the inhibition on topoisomerase I enzyme was studied. The 2'-alkoxymethyl klavuzon derivatives were found to have Topo I enzyme inhibition properties depending on concentration and time manner. The study continued with choices methoxy and isobutoxy derivatives and these two compounds caused an arrest at G1 phase and DNA damage. Also, isobutoxy derivative induced apoptosis in the MIA PaCa-2 pancreatic cancer cell lines.Master Thesis Development of Drug-Loaded Microbubbles for In-Vitro Applications in Cell Biology(Izmir Institute of Technology, 2017) Coşkun, Sema; Özdemir, Ekrem; Sultan Altun, ZekiyeDoxorubicin (DOX) is one of the drugs for cancer therapy. When DOX is used in solution, it affects not only the cancer cells but also the healthy cells. In order to eliminate possible side effects, DOX was encapsulated within liposomes and applied for the cancer therapy. Because the circulation time for liposomes is longer in the body, they accumulate in capillaries, especially at the finger tips and at the toe of the foot called the hand-and-foot syndrome. Here, we proposed to couple the liposomes containing DOX with the microbubbles as the ultrasound contrast agent and deliver the drug to the area of interest. Therefore, DOX was loaded within the liposomes and characterized for their DOX contents. The DOX containing liposomes were conjugated with microbubbles through the avidin-biotin chemistry. It was found that the loaded- DOX content within the liposomes was Langmuir-type. The loaded DOX content increased at lower DOX concentrations and leveled off at higher DOX concentrations. The Langmuir constants can be used in designing DOX loading experiments. The DOX containing liposomes were coupled with the microbubbles and found an optimum of 7.0 for the avidin/biotin mole ratio on the microbubbles. At the optimum avidin/biotin ratio, the conjugated lipo-DOX amount was 3×10-8 μg-DOX/MB. It was concluded that the DOX molecules can be loaded within the liposomes and easily conjugated with the microbubbles and employed in cancer treatments.Master Thesis Investigation of the Effect of 4'-alkylıklavuzon Derivatives on Nucleotide Synthesis and Nucleocytoplasmic Transport(Izmir Institute of Technology, 2016) Kutluer, Meltem; Köksal, Mustafa; Çağır, Ali; Çağır, Ali; Köksal, MustafaIn anti-cancer agent development studies one of the most significant issue is to get an agent that specifically targets cancer cells without any effects on healthy cells. Goniothalamin, that is a styryl lactone isolated from Goniothalamus plant species, is an anti-cancer agent that has selective anti-proliferative activity on cancer cell lines. Klavuzon and derivatives, which can be thought as analogs of goniothalamin, are more cytotoxic in cancer cells compared to goniothalamin. Previous structure activity relationship studies implies that α,β-unsaturated δ-lactone moiety is the source of the biological activity. Since it behaves as Michael acceptor, in this thesis possible irreversible inhibitions of two separate intracellular targets are investigated. In the first part, thymineless death caused by possible thymidylate synthase inhibition has been studied. Anti-proliferative effect of 4’-methylklavuzon in HuH-7 cancer cell line was tested by using MTT. Viability of klavuzon treated cells did not changed significantly in the absence and presence of varying concentration of additional thymidine supplement, and it is concluded that thymineless death is not a crucial mechanism for klavuzon derivatives. In the second part, 4’-methylklavuzon and its derivatives were tested on HeLa cell line to investigate inhibitory effect on the nucleocytoplasmic transport. Immunocytochemistry was used to demonstrate nucleocytoplasmic localization of Riok2 protein which is transferred from nuclei to cytoplasm by CRM1 nuclear export protein. Successfully, all tested klavuzon derivatives inhibit CRM1 nuclear export protein. Potency of the inhibition depends on the size of the alkyl substituent at 4’- position of klavuzon.Master Thesis Invadopodia Formation on Nanometer Scale Protein Patterns(Izmir Institute of Technology, 2014) Batı, Gizem; Pesen Okvur, Devrim; Özyüzer, LütfiHow the positions of invadopodium in the cell are determined and if they have an adhesivefunction are not known. Using fluorescence microscopy and antibodies that recognize actin, cortactin and MT1-MMP proteins, invadopodia formed by breast cancer cells plated on protein nanopatterns of different geometeries and components after stimulation with epidermal growth factor which is known to induce invadopodia formation, were examined. Invadopodia formation was studied for the first time on nanometer scale, single and double active component, protein patterns with equal distance and gradient spacings. The results show that: • On K-casein-fibronectin nanopatterns, invadopodia prefer to form on K-casein which blocks cell adhesion rather than on fibronectin nanodots which promote cell adhesion. • On Laminin-fibronectin nanopatterns, invadopodia prefer to form on laminin rather than on fibronectin nanodots. • On gradient patterns, invadopodia prefer areas with wide spacings. These results support the hypotheses that the positions where invadopodia form can be determined by surface protein nanopatterns and that cell adhesion is not required at points where invadopodia will form.