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Molecular basis of fluoropyrimidine toxic effect etiology with focus on palmar-plantar erythrodysesthesia and potential antidote use
Hartinger, Jan ; Veselý, Pavel (advisor) ; Květina, Jaroslav (referee) ; Brábek, Jan (referee)
(thesis): Palmar-plantar erythrodysesthesia (PPE) frequently accompanies the therapy with a continuous 5-FU infusion or peroral capecitabine (5-FU prodrug). In the most severe cases this adverse effect leads to discontinuation of a needful therapy. Local 10 % uridine ointment is used to prevent and treat the said adverse event. Nevertheless, this method is not generally accepted as an effective one because it has never been proved in a randomized controlled clinical trial. Most probably, a direct effect of a cytostatic compound on the skin of hands and foots causes PPE. The toxicity of 5-FU is mediated primarily by its incorporation into RNA and by thymidylate synthase (TS) inhibition and subsequent DNA synthesis disruption. The importance of particular 5-FU toxicity mechanisms varies in different cell types. For choosing the best PPE local antidote it is necessary to find out which molecular mechanism applies in keratinocytes. We have chosen pyrimidine nucleosides as the most suitable compounds for the local PPE therapy because the uridine ointment is already being used in several oncology centers in the Central Europe. In order to find out the 5-FU toxicity mechanism, we further tested the effect of calciumfolinate (CF) which strengthens the TS inhibition by 5-FU. We studied also uracil and...
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Biological diversity of breast carcinoma cells in relation to the sensitivity on the antitumor treatment
Netíková, Irena ; Veselý, Pavel (advisor) ; Květina, Jaroslav (referee) ; Abrahámová, Jitka (referee)
Biological diversity of cancer cells isolated from breast carcinoma samples has been studied by in vitro exposure to cytotoxic agents. Primary cells from individual primary breast tumours and malignant effusions were in the first phase of the study used for experimental assessment of chemosensitivity/resistance using the standard MTT assay. Cytotoxic effects after short-term cultivation with antineoplastic drugs were evaluated. In several approachable cases relation to the clinical course of the disease was followed; in 4 out of 7 cases good correlation was found. The effect of combination of two cytotoxic drugs on cell viability was studied on EM-G3 cells, showing interesting results with some drug combinations (e.g. combination of paclitaxel and cisplatin resulted in a lower effect than cisplatin alone). Possibility of cell chemosensitisation by tamoxifen pretreatment was tested. Very low chemosensitisation effects of tamoxifen were observed. As a model cell population for diversification development study a new clonal cell line, EM-G3, was established. The EM-G3 line was derived from a primary lesion of human infiltrating ductal breast carcinoma. The EM-G3 represents a unique, spontaneously immortalized clonal cell line, evidently derived from premalignant progenitors of breast carcinoma. The cells are...
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Molecular basis of fluoropyrimidine toxic effect etiology with focus on palmar-plantar erythrodysesthesia and potential antidote use
Hartinger, Jan ; Veselý, Pavel (advisor) ; Květina, Jaroslav (referee) ; Brábek, Jan (referee)
(thesis): Palmar-plantar erythrodysesthesia (PPE) frequently accompanies the therapy with a continuous 5-FU infusion or peroral capecitabine (5-FU prodrug). In the most severe cases this adverse effect leads to discontinuation of a needful therapy. Local 10 % uridine ointment is used to prevent and treat the said adverse event. Nevertheless, this method is not generally accepted as an effective one because it has never been proved in a randomized controlled clinical trial. Most probably, a direct effect of a cytostatic compound on the skin of hands and foots causes PPE. The toxicity of 5-FU is mediated primarily by its incorporation into RNA and by thymidylate synthase (TS) inhibition and subsequent DNA synthesis disruption. The importance of particular 5-FU toxicity mechanisms varies in different cell types. For choosing the best PPE local antidote it is necessary to find out which molecular mechanism applies in keratinocytes. We have chosen pyrimidine nucleosides as the most suitable compounds for the local PPE therapy because the uridine ointment is already being used in several oncology centers in the Central Europe. In order to find out the 5-FU toxicity mechanism, we further tested the effect of calciumfolinate (CF) which strengthens the TS inhibition by 5-FU. We studied also uracil and...
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Molecular basis of fluoropyrimidine toxic effect etiology with focus on palmar-plantar erythrodysesthesia and potential antidote use
Hartinger, Jan ; Veselý, Pavel (advisor) ; Květina, Jaroslav (referee) ; Brábek, Jan (referee)
(thesis): Palmar-plantar erythrodysesthesia (PPE) frequently accompanies the therapy with a continuous 5-FU infusion or peroral capecitabine (5-FU prodrug). In the most severe cases this adverse effect leads to discontinuation of a needful therapy. Local 10 % uridine ointment is used to prevent and treat the said adverse event. Nevertheless, this method is not generally accepted as an effective one because it has never been proved in a randomized controlled clinical trial. Most probably, a direct effect of a cytostatic compound on the skin of hands and foots causes PPE. The toxicity of 5-FU is mediated primarily by its incorporation into RNA and by thymidylate synthase (TS) inhibition and subsequent DNA synthesis disruption. The importance of particular 5-FU toxicity mechanisms varies in different cell types. For choosing the best PPE local antidote it is necessary to find out which molecular mechanism applies in keratinocytes. We have chosen pyrimidine nucleosides as the most suitable compounds for the local PPE therapy because the uridine ointment is already being used in several oncology centers in the Central Europe. In order to find out the 5-FU toxicity mechanism, we further tested the effect of calciumfolinate (CF) which strengthens the TS inhibition by 5-FU. We studied also uracil and...
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Transport Mechanisms of Xenobiotics (Caco-2 Cell Monolayer Model) in Relation to the Biopharmaceutics Classification System (BCS)
Smetanová, Libuše ; Květina, Jaroslav (advisor) ; Štaud, František (referee) ; Suchý, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: MUDr. Libuše Smetanová Supervisor: Prof. RNDr. Dr.h.c. Jaroslav Květina, DrSc., FCMA Title of Doctoral Thesis: Transport mechanisms of xenobiotics (Caco-2 cell mono- layer model) in relation to the Biopharmaceutics Classi- fication System (BCS) Current technological levels enable to study transbarrier transports of xenobiotics (including gastrointestinal absorption) on in vitro, in situ and in vivo models. In situ and in vivo approaches enable to assess feedbacks at the organ or whole body level, in in vitro models extra barrier factors are eliminated and the models are aimed at the mechanisms of transport processes. In vitro models for studying of transport mechanisms through the intestinal wall are derived either from cell lines (e.g., Caco-2, MDCK, 2/4/A1 cells) or intestinal tissues (e.g., Ussing chamber). The Caco-2 cell monolayer model is one of the relatively most frequently used in vitro models. Caco-2 cells are a cell line derived from colorectal adenocarcinoma. The main characteristic is their spontaneous differentiation with the creation of a monolayer of fully differentiated and polarized cells showing typical brush border and tight junctions under normal culture...
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Biological diversity of breast carcinoma cells in relation to the sensitivity on the antitumor treatment
Netíková, Irena ; Veselý, Pavel (advisor) ; Květina, Jaroslav (referee) ; Abrahámová, Jitka (referee)
Biological diversity of cancer cells isolated from breast carcinoma samples has been studied by in vitro exposure to cytotoxic agents. Primary cells from individual primary breast tumours and malignant effusions were in the first phase of the study used for experimental assessment of chemosensitivity/resistance using the standard MTT assay. Cytotoxic effects after short-term cultivation with antineoplastic drugs were evaluated. In several approachable cases relation to the clinical course of the disease was followed; in 4 out of 7 cases good correlation was found. The effect of combination of two cytotoxic drugs on cell viability was studied on EM-G3 cells, showing interesting results with some drug combinations (e.g. combination of paclitaxel and cisplatin resulted in a lower effect than cisplatin alone). Possibility of cell chemosensitisation by tamoxifen pretreatment was tested. Very low chemosensitisation effects of tamoxifen were observed. As a model cell population for diversification development study a new clonal cell line, EM-G3, was established. The EM-G3 line was derived from a primary lesion of human infiltrating ductal breast carcinoma. The EM-G3 represents a unique, spontaneously immortalized clonal cell line, evidently derived from premalignant progenitors of breast carcinoma. The cells are...
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Biotransformation, disposition and toxicological detection of psychedelic phenylalkylamine drugs of abused
Rohanová, Miroslava ; Balíková, Marie (advisor) ; Martásek, Pavel (referee) ; Květina, Jaroslav (referee)
Background: New synthetic drugs known for their psychotropic effects (stimulating, psychedelic and enthactogenic) are drugs of abuse causing number of health and social issues. Together with their consumption the cases of intoxication have increased and therefore the requirements for the differential diagnosis and appropriate therapy have arisen. The aim of the submitted work has been to investigate the disposition and biotransformation profiles of selected synthetic phenylalkylamine derivatives using experimental rats and thus to obtain useful data that might be the base for laboratory diagnostics and appropriate therapy of drug abuse and/or intoxications. These studies have been focused on 2C-B (4-bromo-2,5-dimethoxyphenylethylamine) and PMMA (4-methoxymethamphetamine). (...) Drug concentration levels in blood serum or plasma have been low in relation to much higher tissue concentrations which exceeded multiple times blood concentrations. Proven accumulation abilities of both drugs in lungs and delayed but efficient incorporation with persistence in brain tissue are important pharmacokinetic properties that may explain the delayed onsets and prolonged psychotropic potential. PMMA forms the active psychotropic metabolite PMA that has been, in significant concentrations, present in the brain and together...
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