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Metabolism of inhibitors of tyrosine kinases, the drugs of new generation
Čillíková, Olívia ; Indra, Radek (advisor) ; Kubíčková, Božena (referee)
Cancer is the second major cause of death after heart-attack in the world. In recent years, research has focused on tyrosine kinase inhibitors (TKIs) as part of targeted chemotherapeutic treatment. Vandetanib is a TKI affecting epidermal growth factor receptor (EGFR), rearrangement during transfection (RET) and vascular endothelial growth factor receptor 2 (VEGFR2). It is primary used for treatment of medullary thyroid cancer. Vandetanib is biotransformed by cytochromes P450 and flavin monooxygenases in human organism. Cytochromes P450 (CYPs) oxidaze vandetanib to only one metabolite, N-desmethyl vandetanib, which exhibits similar efficiency as parental molecule. NADPH is the major cofactor of reaction cycle of CYPs. This bachelor thesis studies the effect of various types of cofactors and pH on oxidation of vandetanib by selected human recombinant cytochromes P450, namely CYP2C8 coexpressed with cyt b5, CYP2D6, CYP3A4 and CYP3A4 coexpressed with cyt b5. Here, we investigate the effect of cofactors NADPH, NADH and their mixture in a 1:1 ratio on the amount of N- desmethyl vandetanib formed during the biotransformation of vandetanib. The effect of pH on the oxidation of vandetanib by CYP 3A4 and CYP 3A4 + b5 was also analysed. We analysed the amount of the metabolite formed at the pH range 7 to 8.5...
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Metabolism of inhibitors of tyrosine kinases, the drugs of new generation
Husák, Ondřej ; Indra, Radek (advisor) ; Černá, Věra (referee)
Vandetanib is orally administrated anti-cancer drug that belongs to the class of tyrosinekinase inhibitors which are used for thyroid cancer treatment. This drug undergoes biotransformation and oxidizes into two metabolites - N desmethyl vandetanib and vandetanib N-oxide. The purpose of this bachelor thesis is to compare the potency of vandetanib to vandetanib N- oxide on neroblastome cell line (UKF-NB-4); the study of metabolic process of vandetanib N- oxid and its effect on vandetanib oxidation. In this bachelor thesis we have confirmed the lower potency of vandetanib N-oxide in comparison to vandetanib. We have also discovered that vandetanib N-oxide undergoes further oxidation into another metabolite via microsomes of phenobarbital treated rats. Data suggest that in the presence of vandetanib N-oxide an increased oxidation of vandetanib to N-desmethyl vandetanib occurs. Further experiments have not confirmed this hypothesis. In higher concentrations of vandetanib, the presence of vandetanib N-oxide did not have any effect on oxidation of vandetanib to N-desmethyl vandetanib. The lower concentration led to inhibition of oxidation of vandetanib.
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Thyroid autoimmunity and thyroid nodule elasticity - relation to thyroid nodule biological nature.
Krátký, Jan ; Jiskra, Jan (advisor) ; Gabalec, Filip (referee) ; Smutek, Daniel (referee)
Thyroid nodules represent a very common pathology. Using modern high-resolution ultrasound, nodules could be found in up to 68 % of patients. The most important task is the diagnosis of thyroid cancer which represents only about 5-15 % of nodules, however the incidence is still growing. Even with the use of a fine needle aspiration biopsy, it is not always possible to decide on the biological nature of the nodule. A significant proportion of such patients have to undergo thyroid surgery for diagnostic reason. Thyroid surgery is associated with risks to the patient and financial costs to the health-care system. In recent decades, the efforts to improve non-invasive diagnostics of thyroid nodules have been made. The thyroid elastography and thyroid autoimmunity are among the examined risk parameters. Using real-time strain elastography, thyroid carcinomas elasticity has been significantly reduced compared to benign thyroid nodules in our group of patients. The elastography of thyroid nodules can be used as a suitable complement to conventional sonographic examination. In our work, the combination of both methods (conventional ultrasound and elastography) increased the negative predictive value compared to both methods individually. The results of our work further indicate that, in case of absence of...
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Impact of Differentiated Thyroid Cancer Therapy Using Radioactive Iodine 131 on Salivary Gland Functional Performance
Krčálová, Eva ; Horáček, Jiří (advisor) ; Límanová, Zdeňka (referee) ; Kraft, Otakar (referee)
Background: Although radioactive iodine 131 (RAI) has been successfully used in differentiated thyroid cancer (DTC) patients therapy for more than 70 years, thus far published data regarding RAI- induced salivary glands functional impairment have been inconsistent. Due to the trend towards using lower activities or even RRA omission, the possible RAI untoward effects have been widely discussed. Aim: To evaluate and quantify salivary gland function in thyroidectomised DTC patients before and after RRA using activity of 3.7 GBq and to compare salivary gland functional changes in DTC patients after single or repeated RAI treatment (using activities 5.5 GBq) with their age- and sex-matched RAI-naive counterparts using salivary gland scintigraphy with 99m Tc- pertechnetate. In addition, we performed subjective symptoms evaluation. Patients and Methods: Salivary gland scintigraphy (SGS) was performed in 31 RAI-naive patients (6 men, 25 women, median age 52 years) before and 4.6 months after RRA. Salivary gland function was measured also in 23 patients (7 men, 16 women, median age 60 years) with RAI administration history and compared with their age- and sex-matched counterparts. Non-parametric Wilcoxon and Mann-Whitney tests were used (due to non-normal data distribution) for statistical analysis. A p...
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