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Mitochondria as a target of anticancer therapy.
Dvořák, Aleš ; Ježek, Petr (advisor) ; Poučková, Pavla (referee) ; Vecka, Marek (referee)
Mitochondrial isocitrate dehydrogenase 2 (IDH2) catalyzes reductive carboxylation (RC, reverse Krebs cycle pathway) and 2HG synthesis (2HG) - metabolite of which many scientists are interested. 2HG may be concurrently synthetized in cytosol by IDH1. RC is involved in anabolic reactions necessary for cell proliferation - produces citrate, fatty acid precursor - especially in hypoxia. IDH2 and IDH1 are not the only enzymes that are involved in 2HG synthesis. Recently, several enzymes, which participate in 2HG production, have been discovered. 2HG is useful in cancer diagnostics due to its overproduction by transformed cells. Moreover, 2HG may cause epigenetic changes via inhibition of 2-oxoglutarate dependent dioxygenase. In this work, the importance of RC and 2HG synthesis in cancer and healthy cells was investigated by gas chromatography with mass spectrometry detection as well as IDH2 influence. We found that IDH2 significantly participates in reverse RC and 2HG synthesis in breast cancer cell lines and uses glutaminolysis as a supplementary anaplerotic pathway. RC is increased by hypoxia, inhibition of respiration, and decreased by activation of respiration or hypocapnia. We confirmed 2HG synthesis and RC in healthy cells (fibroblasts, breast epithelial cells etc.) as well as in cancer cells....
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A study on the activity of α-tomatine and newly synthetized derivatives of benzo[c]fluorene
Suchá, Lenka ; Tomšík, Pavel (advisor) ; Pejchal, Jaroslav (referee) ; Poučková, Pavla (referee)
Many of anticancer drugs are of natural origin. Plants from the Solanaceae family contain various steroidal glycoalkaloids that are toxic to cancer cells. The aim of the first part of this work was to evaluate the potential anticancer effect of α-tomatine - a steroidal glycoalkaloid from Solanaceae plant family. The second part of this work was focused on the anticancer research of newly synthetized derivatives of benzo[c]fluorene. Benfluron, one of the derivatives, was reported 30 years ago to have anticancer effects in vitro and in vivo almost. Tomatine inhibited the proliferation and viability of MCF-7 cells. In this cancer cell line treated with tomatine, no DNA damage, no changes in p53 and p21WAF1/CIP1 protein levels, neither the induction of apoptosis was demonstrated. However, the decrease in ATP levels was found. New synthetized derivatives of benfluron and dimefluron caused higher cytotoxic effect in the different cancer cell lines compared with their original compounds. On the other hand, these derivatives did not caused higher tumour growth inhibition when compared with their original compounds in in vivo studies. Benfluron and hydrazone of dimeflurone prolonged the survival of mice with inoculated solid form of Ehrlich tumour. In this work, we demontrated that tomatine did not induce apoptosis...
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Responsive and non-responsive soft matter nanomedicines for biomedical applications
Jäger, Eliézer ; Štěpánek, Petr (advisor) ; Sedláková, Zdeňka (referee) ; Poučková, Pavla (referee)
The thesis outlines possible medical applications of soft matter assemblies as nanotechnology based systems as well as their potential in the emerging field of nanomedicine. Nanomedicine can be defined as the investigation area encompassing the design of diagnostics and therapeutics at the nanoscale, including nanobots, nanobiosensors, nanoparticles and other nanodevices, for the remediation, prevention and diagnosis of a variety of illnesses. The ultimate goal of nanomedicine is to improve patient quality-of-life. Because nanomedicine includes the rational design of an enormous number of nanotechnology-based products focused on miscellaneous diseases, a variety of nanomaterials can be employed. Therefore, the thesis is driven by a focus on recent advances in the manufacture of soft matter-based nanomedicines specifically designed to improve cancer diagnostics and chemotherapy efficacy. It will in particular highlight liposomes, polymer-drug conjugates, drug- loaded block copolymer micelles and biodegradable polymeric nanoparticles, emphasizing the current investigations and potential novel approaches towards overcoming the remaining challenges in the field as well as a brief overview of formulations that are in clinical trials and marketed products. Based on vehicle-related and...
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Contribution to radiodiagnostics and to treatment of chosen pathological lesions of femur in childhood and in adults
Horák, Martin ; Poučková, Pavla (advisor) ; Marek, Josef (referee) ; Vítek, František (referee)
7 Abstract (AJ) Introduction Radiology examination using specialized modern imaging methods, including CT and MRI, is essential in the diagnosis of congenital and acquired diseases of the musculoskeletal system. The first part of the dissertation deals with certain congenital defects of the short femur, known in the literature as proximal femoral focal deficiency (PFFD). This part summarizes our experience with the radiological findings in the preoperative and postoperative period, with the main attention to the vascular supply to the affected area. The second part of the presentation deals with some aspects of autologous chondrocyte transplantation fixed at two different carriers implanted into post-traumatic articular cartilage defects of the distal femur. Radiological findings are evaluated in the relation to the histopathological findings. Objectives The first part of the study after the distribution of patients with PFFD by current commonly used radiographic classification sets the objective in the extent of scans of the hip joints to specify diagnosis PFFD in each patient and to evaluate in detail changes in the area of disability, especially a course of blood vessels. The evaluation of the radiation burden of repeated X-ray measurements was done with respect to the age of the patients. Tissue samples...
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Antitumour efficacy of gels containing liposomes with hydroxy-aluminium phthalocyanine in photodynamic therapy
Kobrle, Pavel ; Poučková, Pavla (advisor) ; Štukavec, Jan (referee)
The targets of the diploma thesis presented here were to establish the antitumour efficacy of a new liposomal product with hydroxy-aluminium phthalocyanine (PC) in photodynamic therapy (PDT) of malignant tumours and determine the optimum time interval between the topical application of the product and PDT (tumour exposure to light). Effects were examined of the PC concentration on the PDT efficacy in a colon carcinoma cell line (SW-620), mammary carcinoma cell line (MDA-MB-231) and human neuroblastoma cell line (UKF NB-3). Hydroxy-aluminium phthalocyanine was employed as a photosensitizer. Outbred athymic female nude CD-1 mice already bearing the above mentioned xenotransplanted tumours were used in the experiments. The area comprising the tumour was exposed to light from a xenon lamp (600-700 nm, 80 J/cm2 ). The results were statistically evaluated, summarized in tables and plotted in graphs. In the diploma work, the liposomal product containing phthalocyanine (9-18 mg/ml) was shown to have considerable antitumour effects in the types of tumours chosen. The optimum time interval for the PDT is of 10 min after the product topical application. Key words: photodynamic therapy; hydroxy-aluminium phthalocyanine; liposomal drug delivery
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Autoflurescence spectroscopy of colorectal carcinoma
Ducháč, Vítězslav ; Horák, Ladislav (advisor) ; Hoch, Jiří (referee) ; Poučková, Pavla (referee)
The submitted dissertation addresses the issue of autofluorescence diagnostics of colorectal carcinoma. The following objectives were set: to verify the possibilities of exploiting the autofluorescence properties of normal colon tissue and tissue changed by tumour to differentiate them and to verify the possibility of using an experimentally created portable measuring set to carry out an "optical biopsy" during the colorectal carcinoma operation. The project solution was divided into three phases: Phase I focused on experimental verification of the fluorescence characteristics of normal colorectal tissue and tissue changed by tumour with the use of argon and a helium-neon laser. The obtained values confirmed the possibility to differentiate not only in terms of quality (change in the spectral curve) but quantity as well (change in intensity of the autofluorescence emission at selected wavelengths). When excited by the He-Ne laser, an approx. 30 a.u. contribution was observed practically throughout the measured interval, the maximum being between 670 - 700 nm, which corresponds to the fluorescence spectre of porphyrins. Normal tissue did not show hardly any activity. When the Ar laser was used, intensity discriminant values ranged only in individual units. Phase II was devoted to verification of the...
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Chelating polymers for the therapy of Wilson's disease
Mattová, Jana ; Poučková, Pavla (advisor) ; Sedláková, Zdeňka (referee) ; Vávrová, Jiřina (referee)
Wilson's disease is a hereditary disorder of copper metabolism, which causes copper accumulation in organism, especially in the liver, kidneys and brain. Current treatment is based on using low-molecular weight copper chelators and high doses of zinc salts. Unfortunately, they can induce some severe side effects due to systemic action. The aim of this thesis is to improve the treatment of Wilson's disease by using of polymeric drug delivery systems. The size of polymer particles in tens of microns should provide non-resorbability of the drug after oral administration. Synthetic microparticles of poly(glycidyl methacrylate-co- ethylene dimethacrylate), natural microcrystalline cellulose and cross-linked chitosan were used as polymer matrices. N,N-di(2-pyridylmethyl)amine, triethylenetetraamine and 8-hydroxyquinoline were selected as specific copper chelators, which can complex copper cations with high efficiency. The principle of the proposed treatment is that the polymeric carrier-bound chelator complex copper directly from the food in digestive tract of the organism. Because of non-resorbability, the entire complex should be eliminated from the body together with stools. This virtually eliminates systemic side effects. The ability of adsorption of copper and the stability of polymer complex under...
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