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Study of effects of tyrosine kinase inhibitors and their metabolites on tumour cell lines
Kolárik, Matúš ; Indra, Radek (advisor) ; Vinklářová, Lucie (referee)
Vandetanib, lenvatinib and cabozantinib are inhibitors of receptor tyrosine kinases approved to treat locally advanced or metastatic thyroid gland, kidney and liver cancers. These multi- kinase inhibitors, inhibit phosphorylation of tyrosine moieties of protein, thus modulate cell signalization in cancer cells. Metabolites of vandetanib, lenvatinib and cabozantinib were detected in vitro as well as in vivo in blood and urine. Cytochromes P450 and flavin monooxygenases were identified as primary enzymes participating in metabolism of these drugs. Literature lacks information regarding pharmacological efficacy of vandetanib, lenvatinib and cabozantinib metabolites. The aim of this diploma thesis was the investigation of pharmacological efficacy of N-oxides of vandetanib, lenvatinib and cabozantinib. The viability measurement under normoxic and hypoxic conditions was employed to determined their efficacy. The expression of enzymes of the first phase of xenobiotics metabolism (CYP 450 1A1, 1B1, 3A4 a CYP 450 oxidoreductase) and receptor tyrosine kinases RET and VEGFR2, as well as mechanism of changes in their expression were investigated using western blotting and flow cytometry. High performance liquid chromatography was utilised to investigate possible metabolism of tyrosine kinase inhibitors and...
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Inhibitors of tyrosine kinases, the anticancer drugs of a new generation, modulate metabolism of ellipticine
Kolárik, Matúš ; Stiborová, Marie (advisor) ; Lengálová, Alžběta (referee)
8 Abstract Ellipticine is a cytotoxic alkaloid that exhibits multiple mechanisms of action such as intercalation into DNA, inhibition of topoisomerase II and activation of apoptosis due to changes in protein p53. The main mechanism of its action is formation of covalent adducts of ellipticine metabolites with DNA. Inhibitors of tyrosine kinases vandetanib, lenvatinib and cabozantinib are anticancer drugs, approved for treatment of advanced metastatic thyroid gland cancer. Mechanism of their action is modulation of cell signalization pathways in cancer cells. The aim of this thesis was investigation whether tyrosine kinase inhibitors can modulate metabolism of ellipticine in vitro, because metabolic activation of ellipticine dictates its pharmacological efficacy. The formation of ellipticine metabolites catalyzed by human and rat microsmes was found. Superosomes™ containing human or rat recombinant cytochromes P450 (CYP) were used to resolve, whether tyrosine kinase inhibitors affect oxidation of ellipticine by these enzymes. Other enzymes tested for possible alteration of formation of metabolites of ellipticine were peroxidases, including thyreoperoxidase. Ellipticine metabolites were separated by HPLC and quantified. Oxidation of ellipticine by human or rat microsomal enzyme systems was inhibited by tested...
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