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Immune response and tumor microenvironment in the treatment with polymer cytotoxic drugs
Malátová, Iva ; Šírová, Milada (advisor) ; Stollinová Šromová, Lucie (referee)
Chemotherapy is still one of the most widely used anticancer therapies. It is mostly about inhibiting the proliferation of rapidly dividing cells, so it is not selective for tumor cells. As a result, many undesirable side effects are associated with chemotherapy. The disadvantageous properties of chemotherapeutics can be largely eliminated by using conjugates of polymers with low molecular weight drugs. An example of such a conjugate is a doxorubicin-linked HPMA polymer. In addition to the properties obtained by polymer binding, such as achieving solubility in aqueous solutions, reducing systemic toxicity, increasing the maximum tolerated dose, or passive targeting by the EPR effect, the fact that doxorubicin induces immunogenic cell death is used in therapy with this drug. It has already been shown that after complete cure of the experimental mice with polymeric conjugates of HPMA with doxorubicin, some mice develop long-term resistance to re-inoculation with a lethal dose of tumor cells. Resistance is specific to the particular line of tumor cells from which the mouse was cured, and CD8+ cytotoxic T cells and IFNγ play an important role. In this work, we monitored changes in the proportion of immune populations and their activation markers after treatment with HPMA-based polymers with doxorubicin...
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The role of indoleamine 2,3-dioxygenase in tumor progression and it's therapeutic targeting
Hrabánková, Klára ; Šírová, Milada (advisor) ; Čermák, Vladimír (referee)
Indoleamine 2,3-dioxygenase (IDO) is an enzyme that is physiologically expressed in many tissues including small intestine, lung, female genital tract and placenta. It is a key enzyme in metabolism of tryptophan and catalyses the first rate-limiting step in the conversion of tryptophan to kynurenine. IDO plays an important role in immune system in fighting against various pathogens. Its expression is actively induced by inflammatory mediators and it has also an immunosuppressive function. Inducible counter-regulation of inflammation is very important for controlling its potential harmful effects. Depletion of tryptophan and production of kynurenines causes local suppression of effector T lymphocytes and activation of regulatory T cells. It can also support differentiation of dendritic cells toward an immunosuppressive phenotype. IDO expression has been observed in several cancer cell types including acute myeloid leukaemia, ovarian cancer or colorectal carcinoma and plays a major role in suppression of anti-tumour immunity. Thus, the inhibition of IDO may improve the efficacy of chemotherapy and immunotherapeutical protocols. Some IDO inhibitors are currently being tested in clinical trials and preliminary results seem promising so that it may become a new anticancer strategy. Key words indoleamine...
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Use of cucurbitacin D for cancer treatment
Malátová, Iva ; Šírová, Milada (advisor) ; Dibus, Michal (referee)
Cucurbitacins are highly oxidized triterpenoids commonly found in plants, especially in the family Cucurbitaceae. There are seventeen types of cucurbitacins and each of them has its derivatives. Cucurbitacins with the most prominent antitumor activity are B, D, E and I. Of these, cucurbitacin B and D are the most common in plants. This work focuses mainly on cucurbitacin D. Cucurbitacin D often induces apoptosis in tumor cells, cell cycle arrest and thereby stops cell proliferation. Indicators of these processes are reduced levels of Bcl-xL, Bcl-2, p21, p27 and cyclins A and B proteins. The main effect of cucurbitacin D on tumor cells is the inhibition of the STAT3 signaling pathway. Whether this pathway is affected at the level of phosphorylation, dimerization, or STAT3 translocation into the nukleus, the result is blocking transcription of genes, which are activated thanks to STAT3 pathway. These are primarily genes that affect tumor growth, angiogenesis, cell invasion, and immune escape. Cucurbitacin D also affects other cell components and processes, such as the NF-κB transcription factor, the enzyme complex of proteasome and inflammasome. However, current knowledge of cucurbitacin D and its mechanism of action is not yet sufficient for its use as an antitumor drug, although the results of its testing...
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The therapeutic potential of mesenchymal stem cells in a mouse experimental model
Hájková, Michaela ; Krulová, Magdaléna (advisor) ; Hrdý, Jiří (referee) ; Šírová, Milada (referee)
Due to their immunomodulatory and regenerative potential, mesenchymal stem cells (MSCs) represent a promising therapeutic tool for cell-based therapy, organ transplantation or tissue engineering. To improve clinical applicability of MSCs, new methods to increase their delivery and efficacy have been tested in the latest years but the mechanism of observed alterations has not yet been described. In the present project we focused on studying the effect of several factors that can significantly affect the therapeutic success of MSC-based treatment. Initially, we analysed the therapeutic effect of MSCs applied locally on nanofiber scaffold with incorporated cyclosporine A (CsA) in a mouse model of allogeneic skin transplantation. Our results indicate that application of MSCs in the presence of CsA direct M1/M2 macrophage polarization towards regulatory phenotype. This phenotype switching is accompanied by decreased production of nitric oxide (NO) and interferon (IFN-) and increase production of interleukin 10 (IL-10), and may result in suppression of the local inflammatory reaction. The next goal of proposed study was to analyse the effect of the treatment based on MSCs combined with immunosuppressive drugs with different mechanism of action on the balance among distinct T cell subpopulations. We...
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Mechanisms of artralgia in targeted therapies for cancer
Mráčková, Monika ; Büchler, Tomáš (advisor) ; Šírová, Milada (referee)
Many targeted anti-tumor therapies result in arthralgia, the non-inflammatory joint pain. The mechanism of pain signaling in arthralgia is not entirely understood but many studies lead to a conclusion that inflammatory cytokines play an important role. Especially interleukin (IL)-6 has been detected in high levels in plasma of patients treated with anti-vascular endothelial growth factor (anti-VEGF) therapy. Although IL-6 seems to be the key factor causing arthralgia, other possible mechanisms have been described. This review focuses on the published data about the correlation between cytokines and cancer-related arthralgia. Possible treatments and future directions are also described.
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Important mechanisms of tumorigenesis and their role in chemoresistance of head and neck cancers
Zlámalová, Viktorie ; Šírová, Milada (advisor) ; Zíková, Martina (referee)
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common malignancy worldwide. Despite improvements in therapeutic outcomes due to advances in surgery, radiotherapy, chemotherapy, and imaging techniques, HNSCC still has high mortality rate. For patients who are not cured with surgery and radiotherapy, there are few effective treatment options. Although HNSCC is heterogeneous in nature, current molecular classification distinguishes only human papilloma virus positive and negative tumors. HNSCC in general are characterized by considerable resistance and high rate of locoregional recurrence. Loss of p53 control pathway and numerous alterations in components of intracellular signaling pathways are consistently observed throughout the majority of HNSCC cases, supporting uncontrolled proliferation. It was proven that common mutations in the HNSCC genome play major role in tumorigenesis as well as in resistance to chemotherapy. The aim of the thesis is to describe the important mechanisms in HNSCC, which are associated with mutations in epidermal growth factor receptor and p53, and those including PI3K/Akt/mTOR and Notch signaling pathways. Association of these pathways with chemoresistance to commonly used drugs and even to advanced targeted therapeutic agents was evidenced by many...
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Possible applications of polymeric nitric oxide donors in treatment of murine experimental tumors
Horková, Veronika ; Šírová, Milada (advisor) ; Krulová, Magdaléna (referee)
Polymer-based drug delivery systems represent one of the promising strategies for successful tumor treatment. Conjugation of a low-molecular-weight drug to a syn- thetic polymer carrier enables targeted drug delivery to tumor tissue/cells and limited systemic toxicity of the drug. The conjugates show extended circulation time, and preferentially accumulate in tumor tissue due to the Enhanced Permeability and Re- tention (EPR) effect. The EPR effect depends on a structural anomaly in tumor neovasculature, and vasodilators were shown to enhance the EPR effect via an in- crease of blood supply in the tumor. Polymer drug carriers based on water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) benefit from variable architecture, drug loading and controlled release. HPMA-based conjugates with cancerostatics have al- ready proved high anti-tumor activity, inducing complete tumor regression followed by resistance to a second tumor challenge in experimental murine models. Three HPMA-based conjugates with organic nitrates (labeled 1, 2, and 3) were pre- pared as polymer donors of nitric oxide (NO) with the aim to intensify the EPR effect, thereby enhancing accumulation of co-administered macromolecular cancerostatics in the tumor. In this study, the conjugates were non-toxic to cancer cells and did not potentiate...
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Myeloid - Derived Suppressor Cell in the Context of Tumor Microenvironment
Košťálová, Monika ; Šírová, Milada (advisor) ; Indrová, Marie (referee)
Today, tumors are considered not only as a complex of genetically mutated cells with pathological function of excessive proliferation, invasiveness and increased viability, but increased attention is paid for the tumor microenvironment created by the tumor itself. This microenvironment generates conditions, which differ from the normal tissues - for example local hypoxia, lactic acidosis and tumor- induced immunosupression - all these abnormalities lead to increased viability of the tumor tissue. Myeloid-derived suppressor cells (MDSCs) seem to be one of the main mediators of the escape from immunosurveillance. MDSCs represent a heterogenous cell population of myeloid origin. In active state, MDSCs produce enhanced amount of reactive oxygen species, nitrogen compounds and arginase, which represent the mechanisms of the suppression of the anti-tumor immune response. That makes MDSCs a promising therapeutic target. However, recent studies also point out the physiological role of MDSCs, which seems to be essential to consider for succesfull MDSCs targeting. Key words: Tumor microenvironment, immunosurveillance theory, immunoediting, myeloid-derived suppressor cells, immunosuppresion in tumors, therapeutic targeting of MDSCs, physiological role of MDSCs Powered by TCPDF (www.tcpdf.org)
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New ferritin nanoparticles for specific targeting of experimental melanoma in mice: in vitro and in vivo tests.
Rajsiglová, Lenka ; Vannucci, Luca Ernesto (advisor) ; Šírová, Milada (referee)
Cancer diseases represent second most frequent cause of death after cardiovascular diseases in Europe. Nowadays used medical treatments like chemotherapy and radiotherapy are nonspecific and cause huge side effects. Various systems to deliver therapy directly inside the tumour microenvironment and reduce side effects are under development. Protein nanoparticles seem to be very promising strategy to achieve that goal. Our group in cooperation with CNR in Rome tested nanoparticles based on heavy chain of human ferritine. These constructs, modified to expose the tumor targeting molecule, were able to be specifically internalised by B16F10 melanoma cells in vitro. They also specifically target and localise at the sites of primary melanoma and lung metastases of different size in mouse in vivo model. These nanoparticles can carry either therapeutic or diagnostic molecules. Thus they represent a suitable candidate for further studies for potential use in clinical praxis as a diagnostic and/or therapeutic agents (theranostics). Powered by TCPDF (www.tcpdf.org)
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