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11 záznamů v Medvik

Výzkumná zpráva

Vliv polyfenolů a chelátů na toxicitu a účinky anthracyklinů a taxanů

Gut, Ivan, 1936-
Autor Autorita
Státní zdravotní ústav
Autor Autorita

Praha : Iga MZ ČR, 2006

Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR

Přeruš. str. : grafy ; 30 cm

we will study effects of polyphenols and chelators on physical, chemical and biochemical interactions of doxorubin and its metabolites with Fe ions and enzymes in ROS production and lipid peroxidation and the protective effects on proteins and lipids effects of polyphenols and chelators on cardiotoxicity of doxorubicin and epirubicin in cardiomyoblasts aimed at finding compounds comparably or more efficient than the cardioprotective drug Cardioxan effects of polyphenols and chelators on the anticancer action of doxorubicin and epirubicin will observe their influence on dose-related induction of apoptosis by anthracyclines and mechanisms of apoptosis induction related to p53 and casapases inhibition by polyphenols of CYP-catalyzed inactivation of taxanes on their effects will be compared with their presumed action on taxane transport by tumor cells and sensitivity to opoptosis in breast cancer cell lines of variou sensitivity

Chceme studovat vliv polyfenolů a chelárorů na fyzikální, chemické a biochemické interakce doxorubicinu a jeho metabolitů s Fe ionty a enzymy buněk při tvorbě ROS a lipoperoxidaci a ochranné účinky na lipidy a bílkoviny různých organel vliv polyfenolů achelárorů na kardiotoxicitu doxorubicinu a epirubicinu budeme sledovat na kardiomyoblastech s cílem zjistit látky srovnatelné či účinnější než kardioprotektivum Cardioxan vliv polyfenolů a chelárorů na protinádorové účinky doxorubicinu a epirubicinu budeme sledovat pomocí jejich účinků na dávkově závislou apoptózu vyvolanou anthracykliny a na mechanismy apoptózy související s p53 a kaspázovými mechanismy vliv inhibice metabolické inaktivace taxanů polyfenoly na účinky taxanů budeme srovnávat s jejich předpokládanými účinky na transport taxanů nádorovými buňkami a sensitivou k apoptóze u různě sensitivních nádorových linií buněk rakoviny prsu

Konspekt
Farmacie. Farmakologie
NLK Obory
farmacie a farmakologie
farmacie a farmakologie
onkologie
gynekologie a porodnictví
NLK Publikační typ
závěrečné zprávy o řešení grantu IGA MZ ČR

Článek

Cytochrome P450 destruction by benzene metabolites 1,4-benzoquinone and 1,4-hydroquinone and the formation of hydroxyl radicals in minipig liver microsomes

Toxicology in vitro. 2007 ; 21 (4) : 566-575.

ISSN 0887-2333
Medvik
Zdroj

Reactive metabolites of benzene 1,4-benzoquinone and 1,4-hydroquinone exert their toxic effects through covalent and/or oxidative damage to DNA and proteins. Since minipigs have been proposed as a suitable model species in toxicological and pharmacological research, the aim of this study was to explore mechanisms by which catechol, 1,4-hydroquinone and 1,4-benzoquinone destroy cytochrome P450 (P450) and induce oxidative stress in minipig liver microsomes. Our second goal was to assess the usefulness of minipig liver microsomes as a model system for the testing of the production of oxidative stress by clinically relevant quinone-containing compounds, e.g. anthracyclines. Of the three benzene metabolites tested, the highest P450 destruction was caused by 1,4-benzoquinone. This destructive effect did not correlate with the production of hydroxyl radicals as measured by ESR spin trapping which was the highest in samples containing 1,4-hydroquinone. Our results confirm previous findings that 1,4-benzoquinone exerts its effect mainly by direct attack on macromolecules while 1,4-hydroquinone rather stimulates the production of reactive oxygen species. Doxorubicin stimulated the production of hydroxyl radicals and the destruction of P450 similarly as 1,4-hydroquinone. Minipig liver microsomes should be further tested as a possibly suitable model system for the testing of potential modulators of the toxicity of doxorubicin.

Článek

Modulation of paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport?

Bioorganic & medicinal chemistry. 2006 ; 14 (13) : 4519-4525.

ISSN 0968-0896
Medvik
Zdroj

We have investigated the effect of 13 flavonoid derivatives on [(14)C]paclitaxel transport in two human breast cancer cell lines, the adriamycin-resistant NCI/ADR-RES and sensitive MDA-MB-435. For this study, we selected representatives of aurones, chalcones, flavones, flavonols, chromones, and isoflavones with known binding affinity toward nucleotide-binding domain (NBD2) of P-glycoprotein and for which no reported work is available regarding paclitaxel transport. Aurones CB-284, CB-285, CB-287, and ML-50 most effectively inhibited P-gp related transport in the resistant line in comparison with chalcones, flavones, flavonols, chromones, and isoflavone derivatives and accordingly increased the accumulation of [(14)C]paclitaxel and decreased its efflux. Those agents efficiently modulated paclitaxel transport in P-gp highly expressing resistant human breast cancer cells and they could increase the efficiency of chemotherapy in paclitaxel-resistant tumors. In contrast, the sensitive cell line responded reversely in that CB-284, CB-285, CB-287, and ML-50 significantly inhibited accumulation of [(14)C]paclitaxel and especially CB-287, which significantly stimulated its efflux. Some, but not all, of the data correlated with the binding of flavonoid derivatives to P-gp, and indicated that even in the P-gp highly expressing NCI/ADR-RES cells, the binding was not the only factor influencing the transport of [(14)C]paclitaxel. Opposite effects of flavonoid derivatives on the P-gp highly expressing and MDA-MB-435 non-expressing cell lines indicate that paclitaxel is not only transported by P-gp and let us assume that Mrp2 or ABCC5 seem to be good transport-candidates in these cells. The inhibition of paclitaxel accumulation and stimulation of its efflux are potentially unfavorable for drug therapy and since they could be due to modulation of drug transporters other than P-gp, their expression in tumors is of great significance for efficient chemotherapy.

Článek

Cell death induced by taxanes in breast cancer cells: cytochrome C is released in resistant but not in sensitive cells

Anticancer research. 2005 ; 25 (6B) : 4215-4224.

ISSN 0250-7005
Medvik
Zdroj

BACKGROUND: The aim of the study was to contribute to our understanding of the mechanisms responsible for the resistance of breast cancer cells to taxanes. MATERIALS AND METHODS: Cell cycle characteristics, DNA fragmentation, p53 and p21(WAF1/CIP1) expression, caspase-3 and caspase-9 activity, cytochrome c release from mitochondria during cell death induction by the taxanes paclitaxel and docetaxel in highly-sensitive MDA-MB-435 and highly-resistant NCI-ADR-RES human breast cancer cells were compared. RESULTS: Approximately 300-fold higher concentrations of the taxanes were required to induce death in resistant NCI-ADR-RES cells than in sensitive MDA-MB-435 cells. Cell death induced by the taxanes in both sensitive and resistant cells was preceded by the accumulation of cells in the G2/M-phase. Neither cell type produced any DNA fragmentation (DNA ladder) typical of regular apoptosis. The p53 and the p21(WAF1/CIP1) levels did not change in sensitive or in resistant cells during cell death induction by the taxanes. The activity of the executioner caspase-3 increased significantly (2 to 2.5-fold) and, similarly, the activity of caspase-9 increased significantly (2 to 3.5-fold) in both cell types. However, cytochrome c was found to be released from mitochondria into the cytosol only in the resistant NCI-ADR-RES cells, but not in the sensitive MDA-MB-435 cells. CONCLUSION: The death induced by the taxanes in the studied breast cancer cells can be characterized as an apoptosis-like death, including caspase-3 and caspase-9 activation but not oligonucleosomal DNA fragmentation. However, the mechanisms of death induction by the taxanes in sensitive MDA-MB-435 cells and resistant NCI-ADR-RES cells differ. Cytochrome c is released from the mitochondria in resistant but not in sensitive cells.

Článek

Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells

Naunyn-Schmiedeberg's archives of pharmacology. 2005 ; 372 (1) : 95-105.

ISSN 0028-1298
Medvik
Zdroj

The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.