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Charles University Faculty of Pharmacy in Hradec Králové Department od Biochemical Sciences Candidate: Bc. Robin Klieber Supervisor: PharmDr. Anna Jirkovská, Ph.D. Title of thesis: The use of RNA interference for the modification of DNA topoisomerase II levels in cancer cells and its influence on the antineoplastic effect of anthracyclines. Topoisomerase II (TOP II) is an enzyme that alters the topological state of the DNA double helix during physiological processes through the formation of transient DNA double strand breaks. Two TOP II isoforms are known: TOP IIα is essential for proper separation of chromosomes in mitotic cells, whereas TOP IIβ is primarily associated with gene transcription. Anthracycline antibiotics (ANT) belong to the group of topoisomerase poisons that stabilize the covalent complex of TOP II and DNA. This prevents the religation of the DNA double strand breaks and thus causes irreversible DNA damage leading to programmed cell death. Although ANTs are frequently administered in various antineoplastic protocols (hematooncological malignancies, hormone-dependent tumors and others), the therapy still possess a high risk of irreversible cardiotoxicity. The mechanism of cardiotoxicity remains unraveled. However, it has been previously discussed that TOP IIβ inhibition could play a...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Pavla Martinková Supervisor: PharmDr. Anna Jirkovská, PhD. Title of diploma thesis: Antiproliferative activity of novel dexrazoxane analogues and their effect on antitumor effectiveness of anthracyclines Athracycline antibiotics (such as daunorubicin, doxorubicin or epirubicin) belong to the most common terapeutics of both solid tumors and hematological malignities. Unfortunately the serious and life-threatening adverse effect cardiotoxicity compromises their clinical usefulness. The only approved protection against anthracycline cardiotoxicity so far is dexrazoxane. Despite the outstanding cardioprotective ability, dexrazoxane use is very limited mainly due to its possible side effects. So we were directed towards synthesis of dexrazoxane analogues with better pharmacological properties. The aim of this diploma thesis was to assess the antiproliferative activity of novel analogues of both dexrazoxane (MK-15 and ES-5) and ADR-925 (JR-159 and KH- TA4) and their influence on the antiproliferative effectiveness of anthracyclines. Moreover, we aimed to study their chelating properties and their inhibition of the topoisomerase II in solution. We tested the antiproliferative activity of...

Despite significant progress in the development of anti-cancer drugs, there is still a need for novel therapeutic strategies that would improve the outcome of cancer patients. Using proteomic technologies and cell lines with different phenotype of p53 tumour suppressor, we monitored cancer cell response to anti-cancer treatment with focus on the development of drug resistance. The different levels of metabolic proteins were identified in our study which may help to explain different anti-cancer activity of drugs with only a subtle difference in structure. More importantly, proteins associated with the development of drug resistance were identified and such expression changes have become a focus of interest. Our findings demonstrate a higher protein level of serine hydroxymethyltransferase, serpin B5 and calretinin in cancer cells resistant to Aurora kinase inhibitors. Such proteins promote the tumour growth with no apparent impact of p53 phenotype whilst voltage-dependent anion-selective channel protein 2 contributes to the development of resistance only in cells with functional p53 which is accompanied by the decreased level of elongation factor 2. On the other hand, cancer cells with loss of p53 appear to amplify alternative mechanisms such as protection against oxidative stress. The results...