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Metabolism of vandetanib by cytochrome P450 expressed in prokaryotic systems
Rodová, Marie ; Indra, Radek (advisor) ; Takácsová, Paulína (referee)
1 Abstract Recently, biologically targeted treatment by another name targeted molecular therapies have begun to be used in the treatment of cancers bearing specific molecular genetic or morphological traits. Vandetanib is an oral anticancer drug that belongs to a group of tyrosine kinases inhibitors. These inhibitors block signal pathway receptors, thereby inhibit growth, stimulate cell death and reduce the spread of cancer. Vandetanib was approved in April 2011 by the US FDA for a treatment of progressive or symptomatic medullary thyroid cancer. It is used in patients with metastatic or inoperable locally advanced cancer. The metabolism of vandetanib was studied in this thesis. Specifically, the kinetics of vandetanib oxidation to N-desmethylvandetanib by human recombinant cytochromes P450 3A4 expressed in the membrane of E. coli (Bactosomes). The effect of the presence of cytochrome b5 and the effect of the level of NADPH: cytochrome P450 reductase activity on the activity of cytochrome P450 3A4 were studied. The demethylated metabolite of vandetanib, N-desmethylvandetanib, was identified and separated by high performance liquid chromatography (HPLC). Enzyme kinetics studies indicate that vandetanib oxidation is affected by both, the level of NADPH:CYP reductase activity and the presence of cyt b5....
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Study of action of anticancer drugs tyrosine kinase inhibitors in a form of nanotransporters
Takácsová, Paulína ; Stiborová, Marie (advisor) ; Černá, Tereza (referee)
Tyrosine kinase inhibitors (TKI) are small organic molecules designed for the targeted cancer therapy. They perform the inhibition of activated receptor tyrosine kinases in tumor cells, that defeats tumor growth, proliferation, metastasis and angiogenesis in tumor tissue. Two TKI, lenvatinib and vandetanib, are used in thyroid cancer treatment. This thesis investigates the ways leading to enhancement of efficiency of these anticancer drugs for therapy. One of the studied anticancer drug - lenvatinib - was investigated to be prepared in a nanoform. Nanoparticles were based on protein apoferritin as well as on lipids. Theoretical model of lenvatinib interaction with an apoferritin cavity, as well as the model of its encapsulation obtained by computer modeling indicated that lenvatinib seems not to be suitable for preparation of apoferritin nanoparticles. Since lenvatinib occurs in its neutral form during preparation of nanoparticles, it does not interact with nanoparticle. The unsuccessful experimental preparation of lenvatinib-loaded apoferritin nanoparticles confirmed that lenvatinib is not suitable for its preparation. However, the theoretical model can serve for screening of other potentially suitable drugs before the experimental nanoparticle preparation. Since the experimental preparation of...
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