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Effect of cancer-associated fibroblasts on the survival, proliferation and invasiveness of cancer cells.
Nováková, Gita ; Anděra, Ladislav (advisor) ; Brábek, Jan (referee)
Tumour microenvironment, in addition to cancer cells themselves, represents important structural and functional part of the tumour. Similarly to the normal organs tumour microenvironment comprises several cell types (fibroblasts, immune cells, endothelial cells etc.) and non-cellular components, particularly extracellular matrix. All of them form favourable conditions for the growth, proliferation, protection from the immune system- mediated destruction and nutrition of cancer cells. Cancer associated fibroblasts (CAFs) represent the most abundant cell type of tumour microenvironment. Their origin can be traced to local normal fibroblasts, endothelial cells or epithelial cells and the transition into the CAFs phenotype is influenced with several factors secreted by cancer cells (particularly TGF-β). In contrast to fibroblasts activated during wound healing newly formed cancer associated fibroblasts expressing α-SMA are not subsequently eliminated from the respektive tissue. They persist and produce a number of pro-tumorigenic factors - SDF-1, HGF, IGF-1, IL-6, VEGF, PDGF-C, TGF-β, MMPs etc. CAFs and their secreted factors target several signalling pathways enhancing basic characteristics of the tumour, so called Hallmarks of Cancer. Cancer associated fibroblasts promote proliferation and invasiveness of...
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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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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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Effects of natural substances on DNA damage and repair capacity in colorectal cell lines
Vodenková, Soňa ; Opattová, Alena ; Čumová, Andrea ; Slíva, D. ; Vodička, Pavel
Colorectal carcinoma)CRC) represents serious ilness with high incidence and mortality worldwide. Generaly, there is a lack of reliable predictive and prognostic biomarkers, implicated late diagnosis. The effectivity of treatment is rather low - about 50%. Main agent used in CRC treatment is 5 fluorouracil (5-FU), alone or in combination with other cytostatics. 5-FU is halogenated pyrimidine, which is or directly incorporated into DNA or disrupts thymidine synthesis in tumour cells. This damage is repaired by base excision repair (BBR) or mismatch repair. The aim of this study is to investigate the effect of 5FU together with extracts of Ganoderma lucidum (GL) and the role of BER in various lines of colorectal cancer cell lines. Results show increased oxidative damage after GL and 5FU+GL treatment and in the same time decrease of DNA repair in colorectal cell lines. This fact could contribute to improve of 5FU efficacy.
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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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Effect of cancer-associated fibroblasts on the survival, proliferation and invasiveness of cancer cells.
Nováková, Gita ; Anděra, Ladislav (advisor) ; Brábek, Jan (referee)
Tumour microenvironment, in addition to cancer cells themselves, represents important structural and functional part of the tumour. Similarly to the normal organs tumour microenvironment comprises several cell types (fibroblasts, immune cells, endothelial cells etc.) and non-cellular components, particularly extracellular matrix. All of them form favourable conditions for the growth, proliferation, protection from the immune system- mediated destruction and nutrition of cancer cells. Cancer associated fibroblasts (CAFs) represent the most abundant cell type of tumour microenvironment. Their origin can be traced to local normal fibroblasts, endothelial cells or epithelial cells and the transition into the CAFs phenotype is influenced with several factors secreted by cancer cells (particularly TGF-β). In contrast to fibroblasts activated during wound healing newly formed cancer associated fibroblasts expressing α-SMA are not subsequently eliminated from the respektive tissue. They persist and produce a number of pro-tumorigenic factors - SDF-1, HGF, IGF-1, IL-6, VEGF, PDGF-C, TGF-β, MMPs etc. CAFs and their secreted factors target several signalling pathways enhancing basic characteristics of the tumour, so called Hallmarks of Cancer. Cancer associated fibroblasts promote proliferation and invasiveness of...
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IGFBP3 expressing rekombinant vaccinia virus used for tumor therapy
Musil, Jan ; Němečková, Šárka (advisor) ; Forstová, Jitka (referee)
IGFBP-3 expressing rekombinant vaccinia viruses used for tumor therapy Insulin-like growth factor-binding protein-3 (IGFBP-3) is a major regulator of endocrine effects of IGF and is capable to suppress the growth of variety of cancer. Several studies have shown that IGFBP-3 can induce the apoptosis of cancer cells via IGF-dependent and IGF-independent mechanisms. In our study, we have constructed recombinant vaccinia viruses (VACV) expressing IGFBP-3 under the control of the early H5 and synthetic early/late (E/L) promoter to investigate the potential effect on cancer growth in our cervical cancer model. We have shown that the expression of IGFBP-3 alone had no effect on tumor growth. On the other hand, the co-expression of IGFBP-3 enhanced the anti-cancer effect of immunization with the fusion protein SigE7LAMP, which gave rise to the anti-cancer immunity directed against HPV16 induced tumors. We have shown that the double-recombinant P13-SigE7LAMP-H5-IGFBP-3 can enhance the protective immune responses against MK16/ABC induced tumors. Furthermore, we have show that both double-recombinant viruses P13-SigE7LAMP-H5- IGFBP-3 and P13-SigE7LAMP-E/L-IGFBP-3 can increase the anti-cancer effect of SigE7LAMP expression in the therapy of TC-1 induced tumors. Key words: IGFBP-3, IGF, VACV, HPV16, E7 oncoprotein,...
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Verification of the possibility of cancer therapy using bacteria Stenotrophomonas maltophilia. Optimization of this therapy, the effect of agonist of signaling receptors.
SVÁČKOVÁ, Petra
Cancerous disease or cancer is a very feared disease, old as the history of mankind itself. Cancer is understood as a lifestyle disease that affects increasing number of people. Statistical surveys show that the problem is more than current and should be paid close attention to. The main objectives of this thesis are to understand the issue of tumor therapy and to verify the possibilities of using a microorganism therapy. The bachelor thesis has a theoretical and an experimental part. The findings were verified in the experimental part and the hypotheses obtained from the research paper were verified in the theoretical part. The theoretical part is focused on understanding a broad topic of cancer, reaching from the definition of what cancer is, how it arises, up to the therapy options. The second section of the theoretical part is focused on tumorous disease therapy using microorganisms. A research has been made regarding the use of bacteria for cancer treatment. Further research has shown that at natural pH the tumor cells are of a negative charge. That means that if there is a bacteria of naturally positive charge and it is applied on the place of tumor, the positively charged bacteria is bound to the negatively charged cell. After such binding an immune response of the organism is followed, fighting not only against the inflammation caused by the bacteria, but also against the tumor cells. The bacterium S. maltophilia seems to be positively charged. To confirm this hypothesis it was necessary to find a bacteria with similar features, size and ability to move like those of S. maltophilia, but charged negatively . The bacterium S. marcescens is the most convenient, also forming part of Colley´s toxin. Experiments were carried out in female mice of inbred strain C57BL/6 from Charles River Laboratories, using cell line of B16-F10 mice melanoma. The cultivation method of the bacterium S. maltophilia and S. marcescens was introduced in the phase of the in vitro experiment. In the first in vivo experiment a hypothesis was confirmed that by the intratumoral application of the vaccine with the inactivated bacterium S. maltophilia the melanoma was affected. The second in vivo experiment verified the hypothesis concerning the negative charge of the tumor cell and the positive charge of the bacterium S. maltophilia. S. marcescens was used as a control bacteria with a negative charge. The experiments monitored both, the growth and the volume of the tumor. The tumors were measured once in two days by means of caliper, which determined the size of the tumor. The volume of the tumor was calculated. Statistical analysis of data was done using Student's t-test in MS Excel program. The survival of mice was evaluated using the Kaplan-Meier test in the Med Calc program. Performing the in vitro experiment the cultivation of both bacteria was introduced in the workplace. The first in vivo experiment where the bacterium S.maltophilia was used confirmed the hypotesis of the positive impact of the intratumorous application of the bacteria on the melanoma. 472 days on the 10.8.2013, after initiation of therapy - 26.4. 2012). The second in vivo experiment confirmed the hypothesis of the effect of the bacteria charge on the size of the tumor. By means of testing the bacterium S. maltophilia and S. marcescens it was confirmed that the bacterium S. maltophilia affects the reduction of the tumor growth much more than the bacterium S. marcescens. The experiments carried out in the thesis confirmed the hypothesis of the positive impact of bacteria charges on their antitumor effect in the treatment of B16-F10 melanoma.
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Proenzyme therapy of sarcoma S-180 and melanoma B16-F10
KAISEROVÁ, Pavlína
The aim of this study was to evaluate the effectiveness of individual (inactive) proenzymes and mixtures thereof in cancer treatment and to compare this treatment with more frequently used therapy based on active proteases. Experiments focused on explanation of possible mechanisms of proenzyme action against tumors are included.
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