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Study of the binding interaction of tyrosine kinase inhibitors with serum albumin
Rodová, Marie ; Indra, Radek (advisor) ; Heidingsfeld, Olga (referee)
Sunitinib and vandetanib are anti-cancer medications prescribed for medullary thyroid cancer (in the case of vandetanib) and for renal cell carcinoma, gastrointestinal stromal tumor, and pancreatic cancer (in the case of sunitinib). They belong to the group of tyrosine kinase inhibitors and act by exhibiting anti-angiogenic effects and by inhibiting tumor cell proliferation and survival through VEGFR. Additionally, vandetanib also inhibits tumor cell survival via EGFR and RET. In the presented thesis, we investigated the binding interaction between serum albumin and the TKIs vandetanib and sunitinib using BSA, HSA, and blood plasma. We examined the differences in interaction between the TKIs and various serum albumins, including pure BSA, pure HSA, and blood plasma, as well as the nature and location of the binding interaction. Additionally, we studied the influence of other ligands on this interaction and the photosensitivity of sunitinib itself. Utilizing spectroscopic techniques, including UV-VIS absorption and fluorescence quenching, we have determined the Stern-Volmer and binding constants, as well as the thermodynamic parameters, for the binding interactions of sunitinib and vandetanib with BSA and HSA. Our results indicate that complex formation occurs between BSA and sunitinib, BSA and...
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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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