ABTS(+)
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Složení fenolové kyseliny kvetoucích výhonků Caragana frutex bylo analyzováno metodou HPLC. Byl stanoven kvantitativní obsah sedm fenolických kyselin a jejich derivátů: kyselina galová, p-hydroxyfenyloctová, chlorogenová, kávová, р-kumarová, trans-ferulová, sinapová). Kyselina sinapová (513,0 μg/g) a kyselina chlorogenová (98,4 μg/g) převládají mezi deriváty kyseliny hydroxyskořicové. Antioxidační aktivita výhonků Caragana frutex stanovená ABTS metodou činila 9368,51 ± 30,07 μg/g, vyjádřeno jako ekvivalent Troloxu.
The phenolic acid composition of flowering Caragana frutex shoots was analyzed by the HPLC method. The quantitative content of seven phenolic acids and their derivatives has been determined: gallic, p-hydroxyphenyl acetic, chlorogenic, caffeic, р-coumaric, trans-ferulic, and sinapic) acids. Sinapic acid (513.0 μg/g) and chlorogenic acid (98.4 μg/g) predominate among phenolic acid derivatives. The antioxidant activity of Caragana frutex shoots determined by the ABTS method equaled 9368.51 ± 30.07 μg/g expressed as Trolox equivalent.
An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon cancer. Numerous Akt-targeted therapies are being developed, the activity of Akt-inhibitors is, however, strongly pH-dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt inhibitor perifosine and the Bcl-2/Bcl-xL inhibitor ABT-737 was tested in colon cancer HT-29 and HCT-116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour-specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon cancer.
- MeSH
- apoptóza MeSH
- fosfatidylinositol-3-kinasy MeSH
- fosforylcholin * analogy a deriváty farmakologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie účinky léků MeSH
- nádorové mikroprostředí MeSH
- nádory tračníku * farmakoterapie MeSH
- protinádorové látky * farmakologie MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
PURPOSE: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. RESULTS: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. CONCLUSION: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.
- MeSH
- časové faktory MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- glutamáty aplikace a dávkování MeSH
- guanin aplikace a dávkování analogy a deriváty MeSH
- hodnocení rizik MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery krev MeSH
- nádory plic krev farmakoterapie mortalita patologie MeSH
- nemalobuněčný karcinom plic krev farmakoterapie mortalita sekundární MeSH
- pemetrexed MeSH
- přežití bez známek nemoci MeSH
- proporcionální rizikové modely MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky farmakokinetika terapeutické užití MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sulfonamidy aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
- Spojené státy americké MeSH
PURPOSE: To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGNS: Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL. RESULTS: By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL. CONCLUSIONS: As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL.
- MeSH
- apoptóza účinky léků MeSH
- bicyklické sloučeniny heterocyklické aplikace a dávkování MeSH
- bifenylové sloučeniny aplikace a dávkování MeSH
- difúzní velkobuněčný B-lymfom klasifikace farmakoterapie genetika patologie MeSH
- harringtoniny aplikace a dávkování MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nitrofenoly aplikace a dávkování MeSH
- piperaziny aplikace a dávkování MeSH
- proliferace buněk účinky léků MeSH
- protein bcl-X biosyntéza MeSH
- protein MCL-1 biosyntéza genetika MeSH
- protoonkogenní proteiny c-bcl-2 biosyntéza genetika MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- sulfonamidy aplikace a dávkování MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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