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Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukemia
Nálevková, Karolína ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Karolína Nálevková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: PharmDr. Aleš Šorf, Ph.D. Title of diploma thesis: Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukaemia. Acute myeloid leukaemia (AML) is a malignant disease of hematopoietic system. Available treatment does not produce suitable results, as the 5-year survival is only about 30%. The primary induction therapy has remained the same for many years - combination of cytarabine and anthracycline, known as "7+3". By karyotyping and immunophenotyping of patients in the last few years, heterogeneity of the disease was confirmed, which also led to the development of targeted drugs. Other factors such as transporters that play a role in drug transport across plasma membranes may affect the treatment outcome. In my diploma thesis, I therefore focused on the effect of selected membrane transporters OCTN1, OCTN2 and ABCC4 on the prognosis and therapy of AML patients. First, we specified the number of transcripts of studied genes using the RT-PCR and ddPCR methods in samples isolated from mononuclear cells of the blood of de...
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The effect of in vitro and ex vivo placental cells stimulation on expression of selected ABC and OATP transporters
Dudičová, Simona ; Čečková, Martina (advisor) ; Jirkovská, Anna (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Simona Dudičová Supervisor: Assoc. Prof. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: The effect of in vitro and ex vivo placental cells stimulation on expression of selected ABC and OATP transporters The placenta is an organ that plays a key role throughout pregnancy for proper fetal development. One of the important functions provided by the placenta is the transport of substances between the mother and the fetus. This transfer of substances enabled mainly by membrane transporters, which are located on the apical and basal membranes of the syncytiotrophoblast. During various physiological or pathological changes in the human body, their expression and amount can vary significantly. Inflammatory reactions that may occur during pregnancy are also related to these changes, and therefore we have addressed this issue and believed that this condition may alter the expression of placental transporters. The aim of this work was to investigate the changes in the expression of membrane transporters using placental cells on BeWo cell lines and placental villous explants that were stimulated by pro-inflammatory mediators. The change in the expression of individual ATP-binding cassettes,...
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Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukemia
Nálevková, Karolína ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Karolína Nálevková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: PharmDr. Aleš Šorf, Ph.D. Title of diploma thesis: Interindividual variability in expression of selected membrane transporters; their impact on prognosis and therapy of patients with acute myeloid leukaemia. Acute myeloid leukaemia (AML) is a malignant disease of hematopoietic system. Available treatment does not produce suitable results, as the 5-year survival is only about 30%. The primary induction therapy has remained the same for many years - combination of cytarabine and anthracycline, known as "7+3". By karyotyping and immunophenotyping of patients in the last few years, heterogeneity of the disease was confirmed, which also led to the development of targeted drugs. Other factors such as transporters that play a role in drug transport across plasma membranes may affect the treatment outcome. In my diploma thesis, I therefore focused on the effect of selected membrane transporters OCTN1, OCTN2 and ABCC4 on the prognosis and therapy of AML patients. First, we specified the number of transcripts of studied genes using the RT-PCR and ddPCR methods in samples isolated from mononuclear cells of the blood of de...
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Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells
Králová, Adéla ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Králová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá Title of Diploma thesis: Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells Fms-like tyrosine kinase 3 (FLT3) inhibitors represent a new generation of drugs in the treatment of acute myeloid leukemia (AML). Standard therapeutic regimen of AML is initiated with induction therapy consisting of cytarabine and anthracyclines. The disadvantage of this combination is emerging resistance often caused by the ABCB1-mediated efflux. Therefore, simultaneous inhibition of FLT3 and ABCB1, which is inhibited by FLT3 inhibitors used in clinical practice, appears to be a beneficial approach to therapy. However, their effectiveness is declining hence the effort to develop new FLT3-inhibiting molecules. The aim of our work was to evaluate whether our two promising new FLT3-inhibiting compounds would inhibit ABCB1 as well. Promyelocyte cells overexpressing ABCB1 (HL60-ABCB1) and parent HL60-par were used in this study alongside AML-derived cell lines (MOLM-13, THP-1, Kasumi-1). Employing accumulation studies on HL60-ABCB1, strong inhibitory effect towards ABCB1 was demonstrated...
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Study on interactions of selected targeted drugs with ABC drug transporters
Svobodová, Markéta ; Hofman, Jakub (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Markéta Svobodová Supervisor: doc. RNDr. Jakub Hofman, Ph.D. Title od diploma thesis: Study on interactions of selected targeted drugs with ABC drug transporters Cancer is one of the most common causes of death and its incidence is constantly increasing. Treatment mainly includes a combination of drug therapy, surgery and radiotherapy. A new approach, with huge potential, is the use of targeted anti-tumor therapy. This approach is based on specific interaction with tumor cells that reduces the negative effects occuring in conventional chemotherapy. Despite intensive research, we still face insufficient response to treatment. The main cause of therapy failure is the emergence of multidrug resistance (MDR) and the formation of metastases. The MDR phenomenon is most often associated with the overexpression of ATP binding cassette (ABC) transporters. These are responsible not only for the excessive efflux of anticancer drugs from cells, but also mainly affect their pharmacokinetics. Inhibition of these transporters increases the intracellular concentration of the cytostatic and provide the ability to modulate MDR. Therefore, one of the aims of this work was to investigate the inhibitory activity of...
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Modern approaches to cancer treatment
Hulová, Lucie ; Štaud, František (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Lucie Hulová Supervisor: Prof. PharmDr. František Štaud, Ph.D. Title of diploma thesis: Modern approaches to cancer treatment Despite the progres of modern medicine cancer diseases are still the second most frequent cause of death in the world. This is due to the still incomplete knowledge of the sources for tumor resistance mechanics, diversity of tumor cells characteristic signs, poor disease prevention as well as late diagnosis. Lack of the resistance mechanics knowledge and attributes characteristics of these tumors led to a number of studies dealing with this issue. These studies revealed some specific properties for number of these tumors, for example occurrence of surface changes of some tumors and activation of certain molecular lines in the cancerous process. This fact gave an impulse to the research and production of substances which selectively kill only tumor cells. This is called a targeted therapy having today an utmost importance in the therapeutic strategy.
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Oxidative stress biomarkers of the erythrocyte in the newborn - a follow-up study
Zubatá, Karolína ; Čečková, Martina (advisor) ; Hronek, Miloslav (referee)
Charles University University of Porto Faculty of Pharmacy in Hradec Králové Faculty of Pharmacy Department of Pharmacology and Toxicology Department of Biological Sciences Student: Karolína Zubatá Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultants: Susana Rocha, Ph.D., prof. Alice Santos-Silva, Ph.D. Title of diploma thesis: Oxidative stress biomarkers of the erythrocyte in the newborn - a follow-up study Increased levels of oxidative stress (OS) have been described in healthy, full-term newborns as a consequence of the drastic changes introduced by birth and by the exposure to extrauterine environment. Our intention was to examine the OS levels in red blood cells (RBCs) of neonates and to further understand the changes that the newborn organism undergoes with its newly- acquired autonomy as this knowledge is limited and there are no reference values. Umbilical cord blood samples were collected from a small population of newborns (n = 8) and several hematological and biochemistry parameters were evaluated. Our experimental data consist of OS biomarkers measurements performed in different fractions of blood (RBC membrane, total RBCs and plasma): membrane bound hemoglobin (MBH), lipid peroxidation (LPO), quantification of catalase (CAT) and glutathione peroxidase (GPx) activities,...
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The role of ABC transporter in clinical practise
Tornová, Petra ; Pávek, Petr (advisor) ; Čečková, Martina (referee)
The role of ABC transporters in clinical practice ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. There are seven subfamilies classified as ABC transporters (ABCA through ABCG) that are expressed in both normal and malignant cells. They are involved in the transport of many substances, including the excretion of toxins from the liver, kidneys, and gastrointestinal tract, and they limit permeation of toxins to vital structures, such as the brain, placenta, and testis. The best-characterized transporter protein is MDR1/P-glycoprotein, and a number of clinical investigations have suggested that its intrinsic or acquired overexpression resulted in a poor clinical outcome of chemotherapy. Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane. Various types of compounds and techniques for the reversal of ABC transporters mediated MDR have been developed, and efforts have concentrated on the inhibition of function and suppression of expression. Increased drug accumulation and...
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The impaired change in plasma long-chain acylcarnitine level as a marker of insulin resistence
Šišmová, Petra ; Nováková, Veronika (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Biophysics and Physical Chemistry Rīga Stradiņš University Latvian Institute of Organic Synthesis Laboratory of Pharmaceutical Pharmacology Candidate: Petra Šišmová Supervisor: Dr. Pharm. Elina Makarova, assoc. prof. Veronika Nováková, Ph.D. Title of the diploma thesis: The impaired change in plasma long-chain acylcarnitine level as a marker of insulin resistance Insulin resistance presents one of the factors that could lead to type 2 diabetes mellitus (T2DM). Increased levels of long-chain (LC)-acylcarnitines are associated with obesity and T2DM and recent studies suggest that LC-acylcarnitines could play a role in the development of insulin resistance. Early diagnosis of insulin resistance would help to prevent the onset of T2DM and the development of associated complications. The purpose of this study was to determine whether the measurements of the changes in acylcarnitine concentrations during the glucose tolerance test (GTT) could be used as a novel marker of insulin resistance. After intraperitoneal administration of glucose in high fat diet (HFD)-fed C57bl/6N, db/db mice and respective controls the concentrations of glucose, insulin, glycated haemoglobin, free fatty acids (FFAs) and acylcarnitine levels in the fasted...
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Current approaches in the treatment of diabetes in pregnancy
Kücük, Pinar ; Čečková, Martina (advisor) ; Vopršalová, Marie (referee)
PINAR KUCUK: Current approaches in the treatment of diabetes in pregnancy. (Diploma thesis) ABSTRACT The management of pregestational diabetes requires tight metabolic control to reduce maternal and perinatal morbidity and mortality. It has been suggested that type I diabetes is a disorder characterized by insulin deficiency and type II diabetes is characterized by insulin resistance. If patient is having type II diabetes, they require higher doses of insulin in pregnancy and limited use of oral hypoglycemic agents; moreover, both type I and type II diabetes mellitus appear to have a necessity of administering different doses of insulin in each trimester. Gestational diabetes mellitus (GDM) is characterized by glucose intolerance of variable severity that begins or is first diagnosed during pregnancy and which shares the same pathophysiology and clinical signs as diabetes mellitus type 2. As well as for a diabetic pregnancy, the therapeutic management of gestational diabetes mellitus must be instituted early and must be intensive. Risk factors for the development of GDM include obesity, older age, family history, previous history of GDM or poor obstetric outcomes, ethnicity, polycystic ovary syndrome and as more recently noted, hypertension. GDM may also be caused by genetic variation that predisposes women...
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