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Interactions of selected anticancer drugs of the MAPK/ERK signaling pathway inhibitors group with the ABC drug transporters
Slatinský, Lukáš ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lukáš Slatinský Supervisor: Assoc. prof. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Interactions of selected anticancer drugs of the MAPK/ERK signaling pathway inhibitors group with the ABC drug transporters ABCB1 (Pgp, P-glycoprotein) and ABCG2 (BCRP, breast cancer resistance protein) are members of a transmembrane efflux ATP dependent transporter family, so called ATP-binding cassettes (ABC). Physiologicaly they are expressed in the cellular membrane and protect body tissues against potentially toxic xenobiotics including drugs. They represent also one of the tumor defense mechanisms when being able to efflux a wide variety of cytotoxic drugs out of the cancer cells leading to treatment failure. BRAF protein plays an important regulatory and signal role in MAPK/ERK pathway affecting cell division, differentiation and secretion. Mutations of BRAF lead to overactivity in MAPK/ERK pathway in many cancer cells and can be therefore targeted by anticancer therapy. Cobimetinib and dabrafenib are relatively new anticancer therapeutics inhibiting the signal pathway mentioned above and they are used in treatment of melanoma carrying the BRAF mutation. The aims of this project were to...
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Testing of the cytotoxicity of potential drugs in the cell lines together with the measurement of their passage through the blood brain barrier by the PAMPA method
Šinaĺová, Lucia ; Hofman, Jakub (advisor) ; Jansová, Hana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucia Šinaľová Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Testing of the cytotoxicity of potential drugs in the cell lines together with the measurement of their passage through the blood brain barrier by the PAMPA method This master thesis focuses on the prediction of tacrine derivatives permeability through blood- brain barrier and their cytotoxicity. We studied tacrine-benzothiazole and tacrine- thiaquinazoline derivates as potential drugs for treatment of Alzheimer's disease. The reason of testing new tacrine derivates was effort to find substances with same effect and lower toxicity, for which was the tacrine discarded from clinical practice. The probable permeability of the studied substances was determined in vitro by the PAMPA method. Based on the permeation coeficient values we have identified that tacrine-benzothiazole derivates A-D (Pe= 8,31- 16,9×10-6 cm/s) and tacrine-thiaquinazoline derivates 1, 3, 4 (Pe= 8,59-14,9×10-6 cm/s) were permeable through blood-brain barrier, tacrine-thiaquinazoline derivate 2 (Pe= 3,79×10-6 cm/s) had uncertain permeability and tacrine-thiaquinazoline derivate 5 (Pe= 2,0×10-6 cm/s) was not permeable. In the pre-clinical evaluation of...
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Study of interactions of antiviral drug tenofovir and its prodrug tenofovir disoproxil fumarate with placental nucleoside transporters
Lalinská, Anežka ; Červený, Lukáš (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Anežka Lalinská Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of interactions of antiretroviral drug tenofovir and its prodrug tenofovir disoproxil fumarate with placental nucleoside transporters Tenofovir (TFV) in the form of ester prodrug tenofovir disoproxil fumarate (TDF) is an essential part of combination antiretroviral therapy. It is often used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in transfer of TFV/TDF from mother to fetus are not described in detail. Since these drugs are nucleoside analogues, there is a possibility that the mechanisms of their transplacental passage might include nucleoside transporters (NTs), either equilibrative or concentrative (ENTs/CNTs). The aim of the diploma thesis was to investigate the role of placental NTs in membrane transfer of TFV and TDF. To address this issue, we performed in vitro accumulation in the BeWo cell line derived from placental choriocarcinoma. By evaluating experiments, we found out that both TFV and TDF might not be substrates of NTs, thus the role of these transporters in TFV/TDF placental pharmacokinetics was not confirmed. Therefore, the drug-drug interactions on NTs...
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Proofs
Hofman, Jakub ; Staněk, Jakub (advisor) ; Rmoutil, Martin (referee)
Title: Proofs Author: Jakub Hofman Department: Department of Mathematics Education Supervisor: RNDr. Jakub Staněk, Ph.D., Department of Mathematics Edu- cation Abstract: This bachelor thesis should clarify the concept of a mathematical proof, briefly describe the individual proof methods and provide examples of proved theorems from various branches of mathematics. Another objective of this thesis is to provide a high school pupil with a study material which with it structure corresponds to mathematical textbooks and lecture notes provided by universities. In the first part of the thesis the basic terms of logic are introduced to the pupil. These are terms a pupil can usually encounter in math classes at school. The knowledge of these terms is essential for understanding the principles of the individual proof methods. The main part of the thesis is focused on explaining the individual proof methods and their application in proving mathematical theorems with di- fficulty appropriate to a pupil of secondary education. The theorems are ordered by the difficulty of their proof; they do not follow from one another nor do they form a coherent mathematical theory as that is not the goal of this thesis. The thesis also contains a list of theorems which a pupil should be ca- pable of proving after being acquainted with...
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Reporter gene studies for nanoparticle mediated DNA and siRNA delivery.
Kovářová, Barbora ; Jirkovská, Anna (advisor) ; Hofman, Jakub (referee)
Charles University, Faculty of Pharmacy in Hradec Králové, Department of Biochemical Sciences University of Vienna, Faculty center for Pharmacy, Department of Pharmaceutical Chemistry, Laboratory of MacroMolecular Cancer Therapeutics Candidate: Barbora Kovářová Supervisor (Charles University): PharmDr. Anna Jirkovská, Ph.D. Supervisor (University of Vienna): Univ. Prof. Dipl. Ing. Dr. Manfred Ogris Co-supervisor (University of Vienna): Dr. Haider Sami, Ph.D. Title of diploma thesis: Reporter gene studies for nanoparticle mediated DNA and siRNA delivery Keywords: transfection, plasmid DNA, siRNA, nanoparticles Gene therapy is a promising field offering potential in several currently incurable diseases. Gene therapy is mediated by modulation of gene expression in specific cells by delivering exogenous nucleic acids. One of current tasks of nucleic acid delivery is exploring several synthetic vectors which would have a potential to overcome the disadvantages of commonly used viral vectors. The present study focused on different types of polyethyleneimine-based nanoparticles for plasmid DNA (pDNA) and small interfering RNA (siRNA) delivery. Integration of imaging contrast agents with gene delivery vehicles is advantageous for tracking the gene delivery process both in vivo and in vitro. Gadolinium...
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Study of ABC drug efflux transporter inhibition by selected tyrosine kinase inhibitors using accumulation methods with cytostatic substrates
Suchá, Simona ; Hofman, Jakub (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Simona Suchá Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study of ABC drug efflux transporter inhibition by selected tyrosine kinase inhibitors using accumulation methods with cytostatic substrates ATP-binding cassette (ABC) drug efflux transporters are transmembrane proteins that utilize the energy from ATP hydrolysis to drive transport of endogenous and exogenous compounds out of the cell. The overexpression of ABC transporters plays a crucial role in the development of multidrug resistance (MDR), a phenomenon responsible for the failure of chemotherapy. Tyrosine kinase inhibitors (TKI) represent novel beneficial therapeutic approach in cancer treatment. TKI block tyrosine kinases which regulate important cellular processes. Deregulation of these enzymes can lead to various types of cancers. In the present work, we investigated interaction potential of selected TKI (alectinib, brivanib, osimertinib, selumetinib) in MDCKII parent cell line and those transduced with human efflux transporters ABCB1, ABCC1 and ABCG2. Using the accumulation studies, we determined the amount of accumulated model substrates (daunorubicin, mitoxantrone) and evaluated the inhibitory effect of...
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The role of biotransformation enzymes in the resistance of cancer cells against standard cytostatics
Giannitsi, Anna ; Hofman, Jakub (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Anna Giannitsi Supervisor: RNDr. Jakub Hofman, Ph.D Title of diploma thesis: The role of biotransformation enzymes in the resistance of cancer cells against standard cytostatics Drug resistance is currently one of the major problems of chemotherapy. Tumor cells are able to defend themselves against the effect of cytostatic drugs due to various mechanisms which leads to a failure of anticancer therapy. The effort to describe new mechanisms of resistance and to develop new therapeutic methods, which would limit this therapeutic obstacle, is logically the subject of many studies. The activity of drug metabolizing enzymes and the subsequent decrease of intercellular concentration of anticancer drugs belongs to one of the possible mechanisms of pharmacokinetic resistance. Enzymes of I. and II. phase of biotransformation participate in this phenomenon. Cytochromes P450, main enzymes of the I. phase, play a major role in the metabolism of many cytostatic agents producing either pharmacologically active or inactive metabolites. Increased expression in tumors and the involvement of individual isoforms into the overall metabolism of cytostatic, which is deactivated by their activity, seems to be one of the...
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Study of interactions of antiviral drug tenofovir and its prodrug tenofovir disoproxil fumarate with placental nucleoside transporters
Lalinská, Anežka ; Červený, Lukáš (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Anežka Lalinská Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of interactions of antiretroviral drug tenofovir and its prodrug tenofovir disoproxil fumarate with placental nucleoside transporters Tenofovir (TFV) in the form of ester prodrug tenofovir disoproxil fumarate (TDF) is an essential part of combination antiretroviral therapy. It is often used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in transfer of TFV/TDF from mother to fetus are not described in detail. Since these drugs are nucleoside analogues, there is a possibility that the mechanisms of their transplacental passage might include nucleoside transporters (NTs), either equilibrative or concentrative (ENTs/CNTs). The aim of the diploma thesis was to investigate the role of placental NTs in membrane transfer of TFV and TDF. To address this issue, we performed in vitro accumulation in the BeWo cell line derived from placental choriocarcinoma. By evaluating experiments, we found out that both TFV and TDF might not be substrates of NTs, thus the role of these transporters in TFV/TDF placental pharmacokinetics was not confirmed. Therefore, the drug-drug interactions on NTs...
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Interactions of selected anticancer drugs of the MAPK/ERK signaling pathway inhibitors group with the ABC drug transporters
Slatinský, Lukáš ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lukáš Slatinský Supervisor: Assoc. prof. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Interactions of selected anticancer drugs of the MAPK/ERK signaling pathway inhibitors group with the ABC drug transporters ABCB1 (Pgp, P-glycoprotein) and ABCG2 (BCRP, breast cancer resistance protein) are members of a transmembrane efflux ATP dependent transporter family, so called ATP-binding cassettes (ABC). Physiologicaly they are expressed in the cellular membrane and protect body tissues against potentially toxic xenobiotics including drugs. They represent also one of the tumor defense mechanisms when being able to efflux a wide variety of cytotoxic drugs out of the cancer cells leading to treatment failure. BRAF protein plays an important regulatory and signal role in MAPK/ERK pathway affecting cell division, differentiation and secretion. Mutations of BRAF lead to overactivity in MAPK/ERK pathway in many cancer cells and can be therefore targeted by anticancer therapy. Cobimetinib and dabrafenib are relatively new anticancer therapeutics inhibiting the signal pathway mentioned above and they are used in treatment of melanoma carrying the BRAF mutation. The aims of this project were to...
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Study of resistance in cancer therapy - protein kinase inhibitors influence on activity of selected human reductases I.
Louvarová, Dagmar ; Wsól, Vladimír (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Dagmar Louvarová Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: Study of resistance in cancer therapy - protein kinase inhibitors influence on activity of selected human reductases I. The anthracycline antibiotics are a significant group of drugs for treatment of various types of cancer. Difficulties related to their usage are cardiotoxicity and multiple drug resistance. Many factors are involved in the development of resistance; one of them is inactivation of anthracyclines by the activity of enzymes, human reductases, which are involved in biotransformation of anthracyclines by reducing their carbonyl group. Daunorubicin was selected from the group of anthracycline antibiotics, in which the potential involvement of selected carbonyl reducing enzymes in its metabolism (AKR1A1, AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C3, AKR1C4, CBR1 and CBR3) was subject of verification. The specific activity of selected reductases was determined by UHPLC analysis of the major metabolite, daunorubicinol. The most active reductases were AKR1B10, AKR1C3, AKR1A1 and CBR1. There is a great potential use of cyclin-dependent kinase inhibitors (CDKi) in cancer therapy. Expected effect is primarily...
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