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Ruthenium-based nanoparticles and testing of their anticancer activity
Žáková, Eliška ; Fohlerová, Zdenka (referee) ; Heger,, Zbyněk (advisor)
Neoplastic diseases hold the second place of the most common causes of death worldwide. Available treatments include various combinations of surgery, chemotherapy, radiation, hormone therapy, immune therapy and targeted therapy. The emphasis is currently laid on nanomedicine, where new nanosized complexes are developed and applied for the targeted treatment and chemotherapy. The aim is to significantly improve the anticancer effect and decrease the damage to organism. In this thesis, ruthenium nanoparticles with a size of 12–14 nm were synthesized and their surface modified with polyvinylpyrrolidone. Furthermore these were subsequently modified with polyoxyethylene(40)stearate for binding of doxorubicin. These nanoparticles were tested on breast carcinoma cells (MDA-MB-231), ovarian carcinoma cells (A2780) and neuroblastoma cells (UKF-NB-4). Apoptosis and necrosis testing showed 60—64 % increase in apoptosis when comparing ruthenium nanoparticles modified with doxorubicin to nonmodified ruthenium nanoparticles. The modification increased level of oxidative stress in tumorous cells and slightly a genotoxicity to non-tumorous cells, nevertheless the hemocompatibility was significantly improved. Testing has proven with IC50 0.98 g/ml, 3.91 g/ml and 1.95 g/ml higher sensitivity to these cells and confirmed expected anticancer activity. Compared to one of the most common chemotherapeutic agents cisplatin the modified ruthenium nanoparticles are significantly more toxic to cell lines A2780 (IC50=21 µg/ml), MDA-MB-231 (IC50=9 µg/ml) and UKF-NB-4 (IC50=4 µg/ml).
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Effect of cancer therapy on fertilization parameters in testicular germ cell tumour patients.
Kruf, Annabelle Elisabeth ; Vondráková, Jana (advisor) ; Nevoral, Jan (referee)
Testicular germ cell tumours (TGCTs) are a rare type of cancer. It is the most common type of cancer in the age group of 15-35 years. The consequences that TGCT and the treatment of this disease impose to these young men in terms of sperm parameters and fertility is yet unclear. This study involves 84 semen samples from 46 patients sorted in three time groups - before treatment, 3 months after the treatment and 6 months after the treatment. Several sperm parameters were studied and compared within the three time points. Adding on to this, the study takes two patients with complete set of semen samples and studies them individually. The results mostly show great differences in patients and this study underlines the individual characteristics that need to be taken into consideration when it comes to patients' fertility journeys after battling TGCT. Sperm viability, concentration, apoptosis, DNA damage, acrosomal integrity and leukocyte concentration nor histone modification evaluation showed any significant changes between said groups. DNA damage was correlated to the level of acrosomal permeability. IgA antibody levels rose significantly in samples after orchiectomy. IgG antibody levels did not show the same trend. A novel approach was optimized and applied using JUNO and FcRL3 double transfected...
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Tumor suppressor NDRG1 and its regulation by iron chelators
Vondráčková, Michaela ; Truksa, Jaroslav (advisor) ; Brábek, Jan (referee)
Iron is an essential trace element required for many processes within a cell, including DNA synthesis and cell cycle progression. Moreover, it is critical for cellular respiration in mitochondria. Due to their proliferative nature, cancer cells are dependent on iron, and depleting this element via iron chelators results in the inhibition of ribonucleotide reductase, leading to cell cycle arrest and apoptosis of cancer cells. Recently, an alternative mechanism for the effect of iron chelators have been proposed, including induction of N-myc downstream regulated gene 1 (NDRG1) expression and its inhibitory effect on c-MET, EGFR, and NF-κB pathways, which can act as oncogenes in a certain context. NDRG1 is a tumour suppressor gene, which is downregulated in many cancers and its downregulation correlates with cancer progression, poor differentiation, and higher metastatic potential. It has been shown that NDRG1 expression can be regulated by intracellular iron - a decrease in intracellular iron leads to upregulation of NDRG1 at mRNA and protein level via the HIF-1-dependent mechanism by inhibiting prolyl hydroxylases. Recently, we have conceived the concept of mitochondrially targeted chelators as an effective anti-cancer agent and in this work, we focused on the evaluation of mitochondrially targeted...
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Ruthenium-based nanoparticles and testing of their anticancer activity
Žáková, Eliška ; Fohlerová, Zdenka (referee) ; Heger,, Zbyněk (advisor)
Neoplastic diseases hold the second place of the most common causes of death worldwide. Available treatments include various combinations of surgery, chemotherapy, radiation, hormone therapy, immune therapy and targeted therapy. The emphasis is currently laid on nanomedicine, where new nanosized complexes are developed and applied for the targeted treatment and chemotherapy. The aim is to significantly improve the anticancer effect and decrease the damage to organism. In this thesis, ruthenium nanoparticles with a size of 12–14 nm were synthesized and their surface modified with polyvinylpyrrolidone. Furthermore these were subsequently modified with polyoxyethylene(40)stearate for binding of doxorubicin. These nanoparticles were tested on breast carcinoma cells (MDA-MB-231), ovarian carcinoma cells (A2780) and neuroblastoma cells (UKF-NB-4). Apoptosis and necrosis testing showed 60—64 % increase in apoptosis when comparing ruthenium nanoparticles modified with doxorubicin to nonmodified ruthenium nanoparticles. The modification increased level of oxidative stress in tumorous cells and slightly a genotoxicity to non-tumorous cells, nevertheless the hemocompatibility was significantly improved. Testing has proven with IC50 0.98 g/ml, 3.91 g/ml and 1.95 g/ml higher sensitivity to these cells and confirmed expected anticancer activity. Compared to one of the most common chemotherapeutic agents cisplatin the modified ruthenium nanoparticles are significantly more toxic to cell lines A2780 (IC50=21 µg/ml), MDA-MB-231 (IC50=9 µg/ml) and UKF-NB-4 (IC50=4 µg/ml).
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