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Interaction of mesenchymal stem cells with immune system and their use in cancer therapy
Sivák, Ladislav ; Kovář, Marek (advisor) ; Paňková, Daniela (referee)
Mesenchymal stem cells (MSC) are multipotent progenitor cells with the ability to differentiate into ectodermal, mesodermal and endodermal cell line. They interact with innate and adaptive immunity and modulate their effector functions. Immunoregulatory effect of MSC results in suppression of inflammatory immune response and induces anti-inflammatory immune response. In addition, MSC have the ability to migrate into tumor site trough soluble factors produced by tumor cells and contribute to tumor growth and metastasis. Preferential homing to site of cancer growth and regulation of immune system make the MSC a promising tool for cancer therapy. Key words: mesenchymal stem cells, immunoregulation, tumors, cancer gene therapy
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Overcoming cancer resistance to chemotherapy through HPMA copolymer conjugates
Sivák, Ladislav
Multidrug resistance (MDR) is a common cause of failure in chemotherapy for malignant diseases. Cancer cells develop MDR most often via the up-regulation of P- glycoprotein (P-gp) expression. P-gp is an efflux pump with broad specificity belonging to ATP-binding cassette (ABC) transporters which decreases the intracellular concentration of various drugs. We designed polymeric conjugates based on an N-(2-hydroxypropyl)methacrylamide (HPMA) bearing a cytostatic drug and/or P-gp inhibitor and tested their cytostatic/cytotoxic activity in vitro and their therapeutic efficacy in vivo in MDR tumors. We demonstrated that HPMA copolymer conjugates bearing both the cytostatic drug (doxorubicin (Dox) or pirarubicin) and the P-gp inhibitor (derivative of reversin 121 (R121) or ritonavir) possess remarkable cytostatic and cytotoxic activity in MDR tumor cell lines in vitro and superior antitumor activity in vivo. Notably, the HPMA copolymer conjugate bearing both Dox and R121 showed significant antitumor activity in both P388/MDR and CT26 mouse tumor models and was capable to completely cure 6 out of 8 mice with established CT26 tumors. We explored the potential of micelle-forming HPMA copolymer-poly(propylene oxide) (PPO) diblock bearing Dox to overcome MDR in vitro and in vivo. The HPMA copolymer-PPO diblock...
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Overcoming cancer resistance to chemotherapy through HPMA copolymer conjugates
Sivák, Ladislav
Multidrug resistance (MDR) is a common cause of failure in chemotherapy for malignant diseases. Cancer cells develop MDR most often via the up-regulation of P- glycoprotein (P-gp) expression. P-gp is an efflux pump with broad specificity belonging to ATP-binding cassette (ABC) transporters which decreases the intracellular concentration of various drugs. We designed polymeric conjugates based on an N-(2-hydroxypropyl)methacrylamide (HPMA) bearing a cytostatic drug and/or P-gp inhibitor and tested their cytostatic/cytotoxic activity in vitro and their therapeutic efficacy in vivo in MDR tumors. We demonstrated that HPMA copolymer conjugates bearing both the cytostatic drug (doxorubicin (Dox) or pirarubicin) and the P-gp inhibitor (derivative of reversin 121 (R121) or ritonavir) possess remarkable cytostatic and cytotoxic activity in MDR tumor cell lines in vitro and superior antitumor activity in vivo. Notably, the HPMA copolymer conjugate bearing both Dox and R121 showed significant antitumor activity in both P388/MDR and CT26 mouse tumor models and was capable to completely cure 6 out of 8 mice with established CT26 tumors. We explored the potential of micelle-forming HPMA copolymer-poly(propylene oxide) (PPO) diblock bearing Dox to overcome MDR in vitro and in vivo. The HPMA copolymer-PPO diblock...
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Overcoming cancer resistance to chemotherapy through HPMA copolymer conjugates
Sivák, Ladislav ; Kovář, Marek (advisor) ; Smetana, Karel (referee) ; Palich Fučíková, Jitka (referee)
Multidrug resistance (MDR) is a common cause of failure in chemotherapy for malignant diseases. Cancer cells develop MDR most often via the up-regulation of P- glycoprotein (P-gp) expression. P-gp is an efflux pump with broad specificity belonging to ATP-binding cassette (ABC) transporters which decreases the intracellular concentration of various drugs. We designed polymeric conjugates based on an N-(2-hydroxypropyl)methacrylamide (HPMA) bearing a cytostatic drug and/or P-gp inhibitor and tested their cytostatic/cytotoxic activity in vitro and their therapeutic efficacy in vivo in MDR tumors. We demonstrated that HPMA copolymer conjugates bearing both the cytostatic drug (doxorubicin (Dox) or pirarubicin) and the P-gp inhibitor (derivative of reversin 121 (R121) or ritonavir) possess remarkable cytostatic and cytotoxic activity in MDR tumor cell lines in vitro and superior antitumor activity in vivo. Notably, the HPMA copolymer conjugate bearing both Dox and R121 showed significant antitumor activity in both P388/MDR and CT26 mouse tumor models and was capable to completely cure 6 out of 8 mice with established CT26 tumors. We explored the potential of micelle-forming HPMA copolymer-poly(propylene oxide) (PPO) diblock bearing Dox to overcome MDR in vitro and in vivo. The HPMA copolymer-PPO diblock...
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Neoangiogenesis as a target for tumor therapy
Vondráčková, Michaela ; Sivák, Ladislav (advisor) ; Dibus, Michal (referee)
Neoangiogenesis associated with tumours is formation of new blood vessels from pre-existing quiescent vessels in surrounding tumour tissue and it results from pathological employment of normal angiogenesis. Neoangiogenesis became a promising target for cancer treatment in spite of its complexity and many pro-angiogenic and anti-angiogenic factors involved in this process. Anti-angiogenic strategies are based on neutralization of angiogenic ligands, their receptors or inhibition of signalling pathways employed by such receptors. Other potential strategies include upregulation or delivery of endogenous inhibitors, inhibition of endothelial cell proliferation, stabilization of basement membrane and direct disruption of tumour vasculature. Many anti-angiogenic agents have been identified in past several decades but only a few of them were approved for clinical use. Anti-VEGF-A monoclonal antibody bevacizumab (Avastin® ), soluble decoy VEGF receptor aflibercept (Zaltrap® ), monoclonal antibody directed against VEGFR-2 ramucirumab (Cyramza® ) and tyrosin kinase VEGFR inhibitors sunitinib (Sutent® ) and sorafenib (Nexavar® ) belong among approved agents. Key words: angiogenesis, neoangiogenesis, anti-angiogenic therapy, HIF-1, VEGF, bevacizumab
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Polymeric conjugates for deliveryof cytostatic drugs and ABC transporter inhibitors in multi drug resistant tumors.
Sivák, Ladislav ; Kovář, Marek (advisor) ; Truksa, Jaroslav (referee)
Significant problem and important cause of failure of the cancer chemotherapy is that even originally very sensitive tumors become resistant to effects of cytostatic drugs. Loss of sensitivity to specific chemotherapeutics agent may not directly cause the loss of sensitivity to other chemotherapeutics. However, it have been described that tumors resistant to one type of chemotherapeutics were found to be resistant to several other anticancer drugs that are different in both structure and mode of action. This phenomenon has been described as multidrug resistance (MDR). MDR can develop in several ways, with the predominant mechanism being the overexpression of ATP- binding cassette (ABC) transporters, such as P-glycoprotein. These transporters acts as energy driven pumps and which, maintain intracellular drug concentration below toxic levels. The aim of this study was to examine the potential of novel polymeric therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing either anticancer drug, inhibitor of ABC transporters or both, for overcoming MDR mediated by P-glycoprotein in doxorubicin (Dox) resistant murine monocytic leukemia cell line P388/MDR. Series of low-molecular weight inhibitors reversin 121 (R121), reversin 205 (R205) and ritonavir (RIT) and their derivatives...
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Interaction of mesenchymal stem cells with immune system and their use in cancer therapy
Sivák, Ladislav ; Kovář, Marek (advisor) ; Paňková, Daniela (referee)
Mesenchymal stem cells (MSC) are multipotent progenitor cells with the ability to differentiate into ectodermal, mesodermal and endodermal cell line. They interact with innate and adaptive immunity and modulate their effector functions. Immunoregulatory effect of MSC results in suppression of inflammatory immune response and induces anti-inflammatory immune response. In addition, MSC have the ability to migrate into tumor site trough soluble factors produced by tumor cells and contribute to tumor growth and metastasis. Preferential homing to site of cancer growth and regulation of immune system make the MSC a promising tool for cancer therapy. Key words: mesenchymal stem cells, immunoregulation, tumors, cancer gene therapy
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