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Sesquiterpenes in cancer therapy
Ambrož, Martin ; Skálová, Lenka (advisor) ; Hodek, Petr (referee) ; Souček, Pavel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Martin Ambrož Supervisor: Prof. RNDr. Lenka Skálová, Ph.D. Title of Doctoral Thesis: Sesquiterpenes in cancer therapy. Chemotherapy is an important part of treatment of cancer. Currently, the use of several anticancer drugs in combination seem to be more advantageous. This combination therapy prevents drug resistance development and make it possible to lower the doses of single drugs, which prevents the side effects in non-cancerous tissues. Large pool of potential drugs for combination therapy can be found among natural compounds, for example among sesquiterpenes. Our project was designed to evaluate the effect of Myrica rubra essential oil (MEO) and selected sesquiterpenes in combination cancer therapy. We focused on the potential ability of MEO and sesquiterpenes to increase the antiproliferative efficacy of classical cytostatics (doxorubicin, oxaliplatin, 5-fluorouracil). In addition, we also studied the possible interaction of sesquiterpenes with other drugs in combination therapy, which could be caused by sesquiterpene-mediated modulation of drug-metabolizing enzymes. For these purposes, a panel of various cell lines (both cancerous and non-cancerous) and primary culture of hepatocytes...
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Biomarkers of prognosis and therapy efficacy in ovarian carcinoma
Cerovská, Ela ; Souček, Pavel (advisor) ; Schierová, Michaela (referee)
Ovarian carcinoma is a serious illness with the highest mortality rate among all female cancers. No suitable methods for early diagnosis, precise determination of prognosis or prediction of therapy efficacy are currently available, which leads to diagnosis in advanced stages of disease and therapy efficacy limitation. Consequently, the development of chemoresistance to conventional drugs and frequent relapse of the disease pose a fundamental complication too. The main goal of the current study was identification of new putative prognostic and therapeutic biomarkers, whose introduction into clinical practice could help to improve the dismal outcome of ovarian carcinoma patients. The present master thesis provides results of expression analysis of genes whose products take part in the transport, metabolism and mechanism of action of platinum based drugs and taxanes, and also the regulation of cell cycle and signaling. Transcript levels of these genes have been assessed in series of tumor and control ovarian tissue samples and the difference between both tissue types was evaluated. Gene expression level in tumors was then compared with patient's clinical data and candidate genes, ABCA2 and PRC1, were selected from the obtained results for more detailed analysis. The protein level of candidate genes...
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Mechanism of enzymatic activation of carcinogens and drugs by the system of cytochrome P450
Indra, Radek ; Stiborová, Marie (advisor) ; Souček, Pavel (referee) ; Koblihová, Jitka (referee)
13 Abstract An environmental pollutant and a human carcinogen benzo[a]pyrene (BaP) is after its activation with cytochrome P450 (CYP) able to covalently bind to DNA. In the thesis, one of the target was to investigate an influence of individual components of mixed function monooxygenase (MFO) system on metabolism of benzo[a]pyrene and generation of adducts of activated BaP with DNA. The study was particularly focused to increase our knowledge on the effect of cyt b5 on metabolism of BaP by cytochrome P450 1A1 (CYP1A1) and its potential to serve as a donor of electrons during the reaction cycle of this cytochrome P450. The effect of cyt b5 on generation of BaP metabolites and adducts of BaP with DNA was investigated. In addition the effect of two different expression systems for cytochrome P450 1A1 (prokaryotic and eukaryotic) was also studied. The influence of cyt b5 on oxidation another xenobiotic compound, a plant alkaloid ellipticine that exhibit antitumor activities, was also investigated. Its pharmacological efficiency, as well as side effects depends on its metabolic activation by cytochrome P450. CYP3A4 is very important for ellipticine activation and therefore this enzyme was used in our experiments. Furthermore, a suitability of rat as a model organism mimicking the metabolic fate of BaP...
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Study of the Sadova area in Brno
Souček, Petr ; Radimský, Michal (referee) ; Matuszková, Radka (advisor)
The diploma thesis focuses on the assessment of transport infrastructure in Brno, the Sadová area and presents a solving proposal for selected problems. The work is based on the site's survey and measurement, as well as data collected from all available sources. The CDV methodology on road safety inspections in accordance with EU Directive 2008/96/EC was used as a basis for processing the analysis of individual sites. A detailed risk assessment is performed at four sites in the area where problems are identified and a proposal for their solution is given. In relation to public transport, the work also evaluates the individual bus stops, identifies major drawbacks, and contains suggestions for a comprehensive solution of bus stops emplacement. The proposal also includes suitable places for the implementation of pedestrian crossings on Kociánka.
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Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors
Vagiannis, Dimitrios ; Hofman, Jakub (advisor) ; Souček, Pavel (referee) ; Zendulka, Ondřej (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Dimitrios Vagiannis Supervisor RNDr. Jakub Hofman, Ph.D. Title of Doctoral Thesis Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors Cancer chemotherapy is an important tool for the cure of cancer. Although the development of new anticancer drugs has been rapidly progressing, the phenomenon of multidrug resistance (MDR) continues to be a key issue leading to therapy failure in oncological patients. MDR is based on pharmacodynamic as well as pharmacokinetic mechanisms. Pharmacokinetic MDR includes drug efflux transporters and biotransformation enzymes that decrease the amount of (active form of) a drug in tumors. While the MDR role of transporters has been well understood, the participation of drug metabolizing enzymes is still unclear. This thesis investigates the role of cytochromes P450 (CYPs) in cytostatic resistance. Furthermore, it focuses on the modulation of pharmacokinetic MDR using pharmacokinetic drug-drug interactions of new targeted antitumor drugs. Finally, it aims to confirm the in vitro findings in ex vivo patient-derived tumor explants. In our latest publication, we demonstrate the significant role of...
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Analysis of cancer predisposition and functional analysis of variants of unknown significance
Stolařová, Lenka ; Kleibl, Zdeněk (advisor) ; Eckschlager, Tomáš (referee) ; Souček, Pavel (referee)
On average, 5-10% of all cancers occur in patients with hereditary tumors, who may have mutations in tens to hundreds of tumor predisposition genes. The phenotypes in mutation carriers overlap, and parallel analyses with sequencing panels is the method of choice in diagnostics. In our laboratory, we designed a universal panel and a targeted panel for a specific cancer, which allowed us to identify genetic alterations in patients with ovarian cancer, breast cancer, melanoma, and other cancers in the Czech Republic. The results of next generation sequencing (NGS) analyses show that the most frequent genetic alteration in ovarian cancers patients in the Czech Republic are hereditary mutations in BRCA1 (in 24% of unselected patients) and in malignant melanoma patients CDKN2A (in 2% of high risk patients). The presence of hereditary alterations is a clinically significant phenomenon affecting the prognosis and treatment of the disease. However, the interpretation of NGS findings is complicated by the presence of variants of unknown significance (VUS). We participate in the interpretation of VUS in the main predisposing genes BRCA1 and BRCA2 within the international consortium ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). Our and international results of the most...
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The role of genetic factors in the prognosis and prediction of effects of the chemotherapy of breast carcinoma
Hlaváč, Viktor ; Souček, Pavel (advisor) ; Hodek, Petr (referee) ; Liška, Václav (referee)
Breast carcinoma is the most common cancer among women in our country and worldwide. One of the obstacles to successful therapy is a multidrug resistance. It can be caused by different factors, such as overexpression of ABC transporters, or decreased expression of SLC transporters, deregulation of drug metabolizing enzymes, variability of the targets of anticancer drugs, failure of apoptosis or increased capacity of repair genes. The aim of this study was to search for associations of genes of drug transport and metabolism with the prognosis of patients or response to chemotherapy. From the view of preventive medicine, this aim constitutes an important part of both secondary and tertiary prevention of cancer, i.e., discovery of markers enabling optimal therapy selection for each patient, decreasing the risk of disease progression to advanced and resistant stage, and elimination of side effects of chemotherapy. The expression profile of ATP-binding cassette (ABC) transporters (49 genes), cytochromes P450 (CYPs, 10 genes), aldo-keto reductases (AKRs, 13 genes) and carbonyl reductase 1 was analyzed in the tumor and adjacent non- tumor control tissues in a cohort of neoadjuvantly treated patients. Genes deregulated in tumors compared with control tissues or genes associated with clinical data were assessed in...
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Role of genetic factors in the prognosis and prediction of efficacy of chemotherapy in breast carcinoma patients
Brynychová, Veronika ; Souček, Pavel (advisor) ; Macůrek, Libor (referee) ; Stružinská, Ivana (referee)
Changes in the regulation of apoptosis and cell cycle are involved in tumor development, progression, and resistance to antitumor therapy. The aim of this work was to evaluate the importance of apoptotic caspases and regulators of cytokineses as possible prognostic and predictive markers in breast carcinoma patients. In addition to determining the transcript levels of selected genes in tumor and control tissues obtained from breast carcinoma patients, we have also focused on the importance of alternative splice variants of caspases and their potential genetially determined regulation. We analysed the obtained data in relation to the clinical-pathological characteristics of the tumors, the progression-free survival of patients and to the response of the patients to the neoadjuvant chemotherapeutic treatment. Part of the work was determination of protein expression levels and verification of the importance of selected candidates for the effect of chemotherapy by functional study. The transcript levels of caspase 2, 3, 7, 8, 9, 10, the specifically detected splice variants caspase 2S, 2L, 3A and B, 3S, 9A, 9B, 8L, and the transcript levels of KIF14 and CIT in breast carcinomas were unrelated to the progression-free survival of patients, or to the response of patients to neoadjuvant treatment. The...
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The study of signaling pathways that modulate multidrug resistance
Dvořák, Pavel ; Souček, Pavel (advisor) ; Daum, Ondřej (referee) ; Benson, Veronika (referee)
The study of signaling pathways that modulate multidrug resistance The theme of cancer cell resistance to anti-cancer drugs including the common mechanisms of resistance development and the theory of cancer stem cells was introduced in the Introduction to the doctoral thesis. The theoretical part was focused more deeply on the two topics - the role of ATP-binding cassette (ABC) transport proteins and chromosomal abnormalities in the development of cancer chemoresistance. The possible therapeutic potential for the treatment of cancer was stressed for both topics. The Results were composed of the commentaries on the five published works, which the author of the thesis conducted as the main author. The first work brought the evidence supporting the hypothesis of the existence of ABC gene expression profiles (signatures), which are common to multiple types of tumors and are associated with significant clinical consequences. These general ABC gene expression profiles could possibly form a new hallmark of cancer. The second work studied more closely a group of acute myeloid leukemia patients, who did not achieve complete cytogenetic remission after two attempts to maintain remission of the malignant disease. The new entity, consisting of patients with the translocation t(2;11)(p21;q23) without the...
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The influence of xenobiotic metabolizing enzymes and transporters on the incidence of colorectal cancer and chemotherapy outcome
Krus, Ivona ; Souček, Pavel (advisor) ; Králíčková, Milena (referee) ; Hodis, Jiří (referee)
Introduction: Colorectal cancer (CRC) is one of the most frequent malignancies and affects approximately 5% of worldwide population. More than 75% of CRC cases represent sporadic forms. Susceptibility to nonhereditary CRC is significantly influenced by polymorphisms and mutations in low-penetrance genes. Variations in biotransformation and DNA repair genes may result in acumulation of toxins and DNA damage in cells leading to the development of cancer. Furthermore, different gene expression profiles of membrane transporters affecting the accumulation of anticancer drugs in tumour cells, e.g. ABC drug transporters, may largely influence inter-individual variability in drug response and chemotherapy outcome. The aim of this study was to evaluate the role of genetic and lifestyle factors in the risk of onset and progression of colorectal cancer. This study followed selected genetic alterations in xenobiotic-metabolizing enzymes (CYP1B1, GSTM1, GSTT1, GSTP1, NQO1 and EPHX1) and genes involved in response to DNA damage (CHEK2 and NBN), as potential CRC susceptibility factors. Another aim of this study was to investigate expression profile of all human ABC transporter genes to follow their prognostic and predictive potential in colorectal carcinoma. Materials and methods: The polymorphisms and other...
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