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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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Study of inter-variant differences in xenobiotics metabolism in flax
Hartinger, Jan ; Skálová, Lenka (advisor) ; Karlíčková, Jana (referee)
Seed root inhibition tests with 18 species of flax (Linum usitatissimum) were carried out with different concentrations of TNT (trinitrotoluene) in order to elucidate intervarietous differences regarding their abilities to degrade nitrocompounds. The curves demonstrating dependency of root lengths on TNT concentrations varied significantly. The outcomes were influenced by the fact that five of the species germinated problematically even with the zero level of TNT. Callus cultures were grown from six of the species and cell suspension cultures were derived from three of them. Cell suspension cultures were tested on the ability to degrade TNT and DNT (dinitrotoluene) present in the medium. The decrease of TNT or, respectively, the decrease of DNT concentrations in the medium was measured by HPLC. It was discovered that contrary to TNT, DNT is very toxic for the cells when its concentrations get close to the level of maximum solubility. Trinitrobenzene, 2-aminodinitrotoluene and 4- aminodinitrotoluene were identified as main degradation products of TNT. Further on, 2D electrophoresis was performed with samples from cultures of two species stressed by DNT and TNT. In case of DNT an increase of protein density was marked in a certain area while in case of TNT no similarity was found between responses...
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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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Study of inter-variant differences in xenobiotics metabolism in flax
Hartinger, Jan ; Skálová, Lenka (advisor) ; Karlíčková, Jana (referee)
Seed root inhibition tests with 18 species of flax (Linum usitatissimum) were carried out with different concentrations of TNT (trinitrotoluene) in order to elucidate intervarietous differences regarding their abilities to degrade nitrocompounds. The curves demonstrating dependency of root lengths on TNT concentrations varied significantly. The outcomes were influenced by the fact that five of the species germinated problematically even with the zero level of TNT. Callus cultures were grown from six of the species and cell suspension cultures were derived from three of them. Cell suspension cultures were tested on the ability to degrade TNT and DNT (dinitrotoluene) present in the medium. The decrease of TNT or, respectively, the decrease of DNT concentrations in the medium was measured by HPLC. It was discovered that contrary to TNT, DNT is very toxic for the cells when its concentrations get close to the level of maximum solubility. Trinitrobenzene, 2-aminodinitrotoluene and 4- aminodinitrotoluene were identified as main degradation products of TNT. Further on, 2D electrophoresis was performed with samples from cultures of two species stressed by DNT and TNT. In case of DNT an increase of protein density was marked in a certain area while in case of TNT no similarity was found between responses...
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