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New inhibitors of topoisomerase II - study of antiproliferative effects and influence on antitumor activity of anthracyclines
Vrobelová, Adriana ; Šimůnek, Tomáš (advisor) ; Jirkovská, Anna (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Adriana Vrobelová Supervisor: prof. PharmDr. Tomáš Šimůnek, PhD. Title of diploma thesis: New inhibitors of topoisomerase II - study of antiproliferative effects and influence on antitumor activity of anthracyclines Despite the dose-limiting cardiotoxicity, anthracyclines (ANT) are among the most effective and widely used antitumor drugs. The only registered drug to prevent this adverse effect is dexrazoxane, whose cardioprotective activity is currently attributed to interaction with topoisomerase 2 (TOP2) beta. This relatively new hypothesis provides an opportunity for the discovery and study of new TOP2 inhibitors, that could be more beneficial cardioprotective drugs. An essential condition for the use of a potential cardioprotective agent is, however, the absence of a negative influence on anticancer efficacy. In this work, we studied the antiproliferative activity of new substances derived from the molecule BNS-22, which is a catalytic inhibitor of TOP2 and manifested cardioprotective activity. We also studied the activity against the antiproliferative effect of daunorubicin (DAU), to clarify the compatibility in case of combined use. These experiments were performed on the leukocytic cell...
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Peripherally substituted subphthalocyanines for photodynamic therapy with benzocrown or tyrosine methyl ester as axial ligands
Hlbočanová, Ingrid ; Macháček, Miloslav (advisor) ; Šimůnek, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Science Candidate: BSc. Ingrid Hlbočanová Supervisor: RNDr. Miloslav Macháček, Ph.D. Title of diploma thesis: Peripherally substituted subphtalocyanines for photodynamic therapy with benzocrown or tyrosine methyl ester as axial ligands Tumor diseases are slowly but surely becoming the most widespread disease in the world. Malignant conditions affect a wide range of people who inherited a predisposition to the disease genetically, or were influenced by environmental factors. However, expensive therapy is a problem not only in developed countries, but especially in third world countries. Financial aspect and availability are only part of the problem. Early diagnosis, prevention before the onset of this type of disease and effective therapy are the key elements to succesfull treatment. Due to the high prevalence and mortality associated with malignant diseases, which are increasing every year, great efforts are devoted to the prevention of these diseases and the correct and timely diagnosis associated with a healthy lifestyle. Great attention is also paid to the research and development of new and effective anti-tumor drugs and therapeutic approaches. One such modern and promising method is photodynamic therapy (PDT)....
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New inhibitors of topoisomerase II - study of antiproliferative effects and influence on antitumor activity of etoposide
Proftová, Lenka ; Šimůnek, Tomáš (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Lenka Ohnemichlová Supervisor: prof. PharmDr. Tomáš Šimůnek, PhD. Title of diploma thesis: New inhibitors of topoisomerase II - study of antiproliferative effects and influence on antitumor activity of etoposide Cancer is a serious societal health problem, which can affect each of us, and its incidence increases rapidly with age. Anthracycline antibiotics (ANT) are extremely effective drugs that have been used to treat a number of cancers. They have a multimodal mechanism of action, one of them being the inhibition of topoisomerase 2 (TOP2), an essential cellular enzyme modulating DNA topology. Currently, use of ANTs is limited due to concerns about the occurrence of cardiotoxicity. Etoposide (ETO) is an antitumor agent that acts as topoisomerase poison. ETO is often used in combination therapy with ANTs, but it is not considered significantly cardiotoxic. Dexrazoxane (DEX) is the only approved cardioprotectant against cardiotoxicity of ANTs. However, it does not act as chelating agent, as previously thought, but through inhibition of TOP2. Although DEX has been shown to be a very potent cardioprotectant, it also has its disadvantages. DEX has been associated with the occurrence of secondary...
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New inhibitors of topoisomerase II - study of antiproliferative effects and influence on antitumor activity of anthracyclines
Vrobelová, Adriana ; Šimůnek, Tomáš (advisor) ; Jirkovská, Anna (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Adriana Vrobelová Supervisor: prof. PharmDr. Tomáš Šimůnek, PhD. Title of diploma thesis: New inhibitors of topoisomerase II - study of antiproliferative effects and influence on antitumor activity of anthracyclines Despite the dose-limiting cardiotoxicity, anthracyclines (ANT) are among the most effective and widely used antitumor drugs. The only registered drug to prevent this adverse effect is dexrazoxane, whose cardioprotective activity is currently attributed to interaction with topoisomerase 2 (TOP2) beta. This relatively new hypothesis provides an opportunity for the discovery and study of new TOP2 inhibitors, that could be more beneficial cardioprotective drugs. An essential condition for the use of a potential cardioprotective agent is, however, the absence of a negative influence on anticancer efficacy. In this work, we studied the antiproliferative activity of new substances derived from the molecule BNS-22, which is a catalytic inhibitor of TOP2 and manifested cardioprotective activity. We also studied the activity against the antiproliferative effect of daunorubicin (DAU), to clarify the compatibility in case of combined use. These experiments were performed on the leukocytic cell...
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Peripherally substituted subphthalocyanines for photodynamic therapy with benzocrown or tyrosine methyl ester as axial ligands
Hlbočanová, Ingrid ; Macháček, Miloslav (advisor) ; Šimůnek, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Science Candidate: BSc. Ingrid Hlbočanová Supervisor: RNDr. Miloslav Macháček, Ph.D. Title of diploma thesis: Peripherally substituted subphtalocyanines for photodynamic therapy with benzocrown or tyrosine methyl ester as axial ligands Tumor diseases are slowly but surely becoming the most widespread disease in the world. Malignant conditions affect a wide range of people who inherited a predisposition to the disease genetically, or were influenced by environmental factors. However, expensive therapy is a problem not only in developed countries, but especially in third world countries. Financial aspect and availability are only part of the problem. Early diagnosis, prevention before the onset of this type of disease and effective therapy are the key elements to succesfull treatment. Due to the high prevalence and mortality associated with malignant diseases, which are increasing every year, great efforts are devoted to the prevention of these diseases and the correct and timely diagnosis associated with a healthy lifestyle. Great attention is also paid to the research and development of new and effective anti-tumor drugs and therapeutic approaches. One such modern and promising method is photodynamic therapy (PDT)....
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Study of the novel phtalocyanines for the vascular-targeted photodynamic therapy of tumors
Brázdová, Petra ; Macháček, Miloslav (advisor) ; Šimůnek, Tomáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Petra Brázdová Supervisor: Mgr. Miloslav Macháček Title of diploma thesis: Study of the novel phthalocyanines for the vascular-targeted photodynamic therapy of tumors Cancer is one of the leading causes of death in developed countries, therefore a big effort is devoted on research of novel anticancer drugs. Photodynamic therapy (PDT) is currently a well-established method in this area, but targeting its effect on tumor vasculature has not been considered until recently. In comparison with PDT, vascular-targeted photodynamic therapy (VTP) takes the advantage of a much shorter interval between administration of the photosensitizer (PS) and irradiation (drug-light interval) and thus turning the effect of cytotoxic agents to tumor vasculature. It is intended to disrupt the oxygen and nutrients supply to malignant cells and thus cause their damage and death. Aim of this work is to evaluate the efficacy of newly synthesized PSs from the group of phthalocyanines and azaphthalocyanines using the VTP protocol under in vitro conditions. The PSs used in this study have been investigated recently with classical PDT protocol, in which they have demonstrated very promising activity against tumor cells...
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Hereditary hemochromatosis - Importance of molecular biology analysis of S65C mutation in HFE gene
Putzová, Daniela ; Beránek, Martin (advisor) ; Šimůnek, Tomáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Daniela Putzová Supervisor: Doc. PharmDr. Martin Beránek, Ph.D. Title of diploma thesis: Hereditary hemochromatosis - Importance of molecular biology analysis of S65C mutation in HFE gene Background: The aim of this work was to establish an investigative method PCR-RFLP for the detection of the mutation S65C in HFE gene which can be used for an analysis of real clinical samples and for determination of their S65C mutation occurrence. Methods: In this study, 140 samples from patients were analyzed (68 % (n = 95) of samples from men, 32 % (n = 45) from women, in the age from 20 to 83 years) for the presence of the mutation S65C in HFE gene using PCR-RFLP method. For amplification of required segments of HFE gene, primers (5'- ACA TGG TTA AGG CCT GTT GC - 3', 5'- GCC ACA TCT GGC TTG AAA TT - 3') were used. The enzyme HInfI was used for the restriction analysis. Results: S65C mutation allelic frequency was determined as 1.8 % in this cohort of patients. Five patients (3.6 %) were heterozygous for the mutation S65C; two of them (1.4 %) were identified as C282Y/S65C compound heterozygotes. Conclusions: PCR - RFLP procedure was successfully established for the determination of S65C mutation...
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