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The effect of tyrosinkinase inhibitors vandetanib and lenvatinib and cytotoxic alkaloid ellipticine on biotransformation enzymes
Baráčková, Petra ; Dračínská, Helena (advisor) ; Václavíková, Radka (referee)
In recent years, tyrosine kinase inhibitors have been widely used for the treatment of certain tumors as so-called targeted therapy. Many studies are concerned with their metabolism and the role of enzymes in the biotransformation process, but very little is known about the impact of tyrosine kinase inhibitors on the expression and activity of biotransformation enzymes. Nevertheless modification of the expression and activity of enzymes may cause adverse interactions of co-administered drugs and their negative impact on the human body. This diploma thesis studies the effect of tyrosine kinase inhibitors vandetanib and lenvatinib and cytotoxic alkaloid ellipticine on biotransformation enzymes in a rat model organism in vivo. The aim was to characterize the effect of the investigated compounds on gene expression, protein expression and activity of cytochromes P450 (CYP) 1A1, 1A2 and 1B1 and flavin-containing monooxygenases FMO1 and FMO3 in renal and hepatic microsomes. Microsomes and RNA were isolated from kidneys of control rats and the pretreated rats. Western blot and immunodetection was used to compare the protein expression levels of studied enzymes in kidney and liver. By reverse transcription, cDNA was prepared from isolated RNA and used as a template for quantitative PCR to compare the...
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Gene therapy of cystic fibrosis
Baráčková, Petra ; Bořek Dohalská, Lucie (advisor) ; Nosková, Libuše (referee)
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the membrane protein called cystic fibrosis transmembrane conductance regulator (CFTR). It is the most frequent genetic disease in Caucasian populations. It currently affects approximately 75,000 individuals worldwide. CF as a monogenic disease represents an appropriate target for the gene therapy. Since the sequencing of the CFTR gene in 1989, a large number of preclinical and clinical studies have been performed examining the various principles of this therapy. The aim of this review study is to summarize the findings and introduce the latest strategies of the gene therapy of cystic fibrosis, which represent a promising basis for definitive cure of this disease. The evolving technologies of genomic engineering, deepening knowledge in pathogenesis of this disease and the results of preclinical and clinical trials motivate researches to further testing of the gene therapy strategies, which have the potential to eliminate the cause of the disease and cure it by intervening in human genome. Keywords: cystic fibrosis, CFTR gene, CFTR protein, gene therapy
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