STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS

CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF BIOCHEMICAL SCIENCES Candidate: Mgr. Hana Jansová Supervisor: Doc. PharmDr. Tomáš Šimůnek, Ph.D. Title of Doctoral Thesis: STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS Development of cardiovascular disorders is associated with various risk factors and oxidative stress plays an important role in many of them. Iron-catalysed production of highly toxic and reactive hydroxyl radicals may contribute to oxidative stress. Chelation of free iron seems to be a promising strategy to prevent the propagation of oxidative stress. However, the use of classic iron chelators in pathological conditions without iron overload is associated with the risk of toxicity due to the iron depletion. Hence, this study deals with cardioprotective properties of iron chelators as well as prochelators derived from them. We focused on prochelators with almost no affinity for iron ions until they are activated under disease-specific oxidative stress conditions. For a long time, it has been assumed that oxidative stress is also the main denominator in an anthracycline-induced cardiotoxicity. However, the previous studies suggested alternative mechanism(s). Therefore in the..

Ethical education at the Curie´s Primary School in Prague

The master thesis concerns itself with theoretical and practical aspects of ethical education. Further, it describes the project of ethical education as implemented at the primary school Curieových in Prague in relation to individual theoretical concepts, which are used in this project, in particular the concept of ethical education according to R. R. Olivar and L. Lencz and drama in education. Part of the thesis is also the reflection of the specific features of the project and its consequences. The thesis raises the question what is the long-term effect of realization of the project on the climate of the school and the behaviour of the children. Part of the thesis is extensive annexes, which contain in particular records of programs of ethical education lessons, photo-documentaion and interviews with teachers

Ethical education at the Curie´s Primary School in Prague

Diplomová práce se věnuje teoretickým i praktickým aspektům etické výchovy. Dále popisuje projekt etické výchovy, jak je realizován na ZŠ Curieových v Praze ve vztahu k jednotlivým teoretickým koncepcím, které tento projekt využívá. Mezi ně patří zejména koncepce etické výchovy podle R.R.Olivara a L.Lencze a dramatická výchova. Součástí práce je zamyšlení nad specifiky uvedeného projektu a jejich důsledky. Práce si klade otázku, jaký dlouhodobý vliv má realizace projektu na atmosféru školy a chování žáků. Součástí práce je obsáhlý přílohový materiál, který mimo jiné zahrnuje záznamy programů lekcí etické výchovy, fotodokumentaci a rozhovory s pedagogy

STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS

CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF BIOCHEMICAL SCIENCES Candidate: Mgr. Hana Jansová Supervisor: Doc. PharmDr. Tomáš Šimůnek, Ph.D. Title of Doctoral Thesis: STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS Development of cardiovascular disorders is associated with various risk factors and oxidative stress plays an important role in many of them. Iron-catalysed production of highly toxic and reactive hydroxyl radicals may contribute to oxidative stress. Chelation of free iron seems to be a promising strategy to prevent the propagation of oxidative stress. However, the use of classic iron chelators in pathological conditions without iron overload is associated with the risk of toxicity due to the iron depletion. Hence, this study deals with cardioprotective properties of iron chelators as well as prochelators derived from them. We focused on prochelators with almost no affinity for iron ions until they are activated under disease-specific oxidative stress conditions. For a long time, it has been assumed that oxidative stress is also the main denominator in an anthracycline-induced cardiotoxicity. However, the previous studies suggested alternative mechanism(s). Therefore in the..

In vitro study of antiproliferative effects of selected topoisomerase II inhibitors

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Hana Jansová Supervisor: Doc. PharmDr. Tomáš Šimůnek, Ph.D. Title of diploma thesis: In vitro study of antiproliferative effects of selected topoisomerase II inhibitors. Anthracycline antibiotics (such as doxorubicin or daunorubicin) are antineoplastics which act as the topoisomerase II poisons. They stabilize a reaction intermediate in which DNA strands are cut and covalently linked to tyrosine residues of topoisomerase II, eventually impeding DNA resealing. Failure of relaxing the supercoiled DNA results in block of DNA replication and transcription. Doxorubicin is used for the treatment of solid tumours as well as haematologic malignancies, while daunorubicin can be used to treat specific types of leukaemia. Unfortunately, cardiotoxicity represents serious side effect of these drugs. Therefore, combinations of anthracyclines with cardioprotective agent dexrazoxane are sometimes used. The proposed mechanism of dexrazoxane cardioprotective action is chelation of the iron ions which decrease the production of reactive oxygen species. Dexrazoxane is also a catalytic inhibitor of the topoisomerase II and there are doubts, whether it may compromise the antitumour effectiveness of the..

Evaluation of human thorax FE model in various impact scenarios

The study focused on the validation of the 50 th percentile male model — a detailed FE model of the thoracic segment of the human body developed within project Development of a Finite Element Model of the Human Thorax and Upper Extremities (THOMO) co-funded by the European Commission (7 th Framework Programme). The model response was tested in three impact scenarios: frontal, lateral and oblique. The resulting impactor contact force vs. time and chest deflection vs. time responses were compared with experimental results. The strain profile of the 5th rib was checked with lateral and oblique strain profiles from post-mortem human subject (PMHS) experiments. The influence of heart and lungs on the mechanical response of the model was assessed and the material data configuration, giving the most biofidelic thorax behaviour, was identified

In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites.

Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents