TNF-related apoptosis-inducing ligand (TRAIL) is a proapoptotic cytokine implicated in cancer cell surveillance. A potential of TRAIL as a cancer-specific therapeutic agent has been proposed, either as a single agent or in combination with chemotherapy. Prolonged exposure of TRAIL-sensitive leukemia cell line, wild-type (WT) HL60 cells to recombinant soluble TRAIL or to cytostatic agents, cytarabine and idarubicin, resulted in the establishment of resistant subclones with distinct phenotypic features. The TRAIL resistant HL60 subclones were characterized by decreased expression of TRAIL and TNFalpha death receptors. These resistant subclones had impaired activation of caspases 8 and 10 in response to TRAIL and TNFalpha, decreased TRAIL-induced nuclear translocation of NFkappaB RelA/p65, and dysregulation of the expression of several apoptosis regulators. Among the TRAIL resistant HL60 subclones we identified two separate phenotypes that differed in the expression of CD14, osteoprotegerin, and several apoptosis regulators. Both these TRAIL resistant HL60 subclones were resistant to TNFalpha, suggesting disruption of the extrinsic apoptotic pathway, but not to cytostatic agents, cytarabine and idarubicin. The concurrently derived HL60 subclones were cytarabine and idarubicin-resistant but remained sensitive to TRAIL-induced apoptosis. We identified distinct pathways for the development of HL60 leukemia cell resistance to apoptosis induction. These findings are relevant for the design of more effective strategies for leukemia therapy.

• MeSH
• akutní promyelocytární leukemie metabolismus   patologie   MeSH
• apoptóza MeSH
• chemorezistence MeSH
• cytarabin farmakologie   MeSH
• financování organizované MeSH
• HL-60 buňky MeSH
• idarubicin farmakologie   MeSH
• kaspasy metabolismus   účinky léků   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protein TRAIL farmakologie   MeSH
• protein-serin-threoninkinasy metabolismus   účinky léků   MeSH
• proteiny regulující apoptózu metabolismus   účinky léků   MeSH
• receptory TNF metabolismus   účinky léků   MeSH
• rekombinantní proteiny farmakologie   MeSH
• TNF-alfa farmakologie   MeSH
• TRAIL receptory metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that can trigger apoptosis in many types of human cancer cells via engagement of its two pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). TRAIL can also activate several other signaling pathways such as activation of stress kinases, canonical NF-κB signaling and necroptosis. Though both receptors are ubiquitously expressed, their relative participation in TRAIL-induced signaling is still largely unknown. To analyze TRAIL receptor-specific signaling, we prepared Strep-tagged, trimerized variants of recombinant human TRAIL with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, we examined the contribution of individual pro-apoptotic receptors to TRAIL-induced signaling pathways. We found that in TRAIL-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeds comparably via both DR4- and DR5-activated signaling. TRAIL-induced apoptosis, enhanced by the inhibitor of the Bcl-2 family ABT-737, or by the translation inhibitor homoharringtonine, proceeded in both cell lines predominantly via the DR5 receptor. ShRNA-mediated downregulation of DR4 or DR5 receptors in HT-29 cells also pointed to a stronger contribution of DR5 in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was activated similarly by both DR4- or DR5-specific ligands. Activation of auxiliary signaling pathways involving NF-κB or stress kinases proceeded under apoptotic conditions mainly in a DR5-dependent manner, while these signaling pathways were during necroptosis similarly activated by either of these ligands. Our study provides the first systematic insight into DR4-/DR5-specific signaling in colorectal and pancreatic cancer cells.

• MeSH
• apoptóza genetika   MeSH
• buňky HT-29 MeSH
• kaspasa 8 genetika   MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• malá interferující RNA MeSH
• nádory slinivky břišní genetika   patologie   MeSH
• nekróza genetika   patologie   MeSH
• NF-kappa B genetika   MeSH
• pankreas metabolismus   patologie   MeSH
• proliferace buněk genetika   MeSH
• protein TRAIL genetika   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce genetika   MeSH
• TRAIL receptory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mantle cell lymphoma (MCL) is a rare aggressive type of B-cell non-Hodgkin's lymphoma. Response to chemotherapy tends to be short and virtually all patients sooner or later relapse. The prognosis of relapsed patients is extremely poor. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered one of the novel experimental molecules with strong antitumor effects. TRAIL triggers extrinsic apoptotis in tumor cells by binding to TRAIL 'death receptors' on the cell surface. Recombinant TRAIL has shown promising pro-apoptotic effects in a variety of malignancies including lymphoma. However, as with other drugs, lymphoma cells can develop resistance to TRAIL. Therefore, the aim of this study was to identify the molecular mechanisms responsible for, and associated with TRAIL resistance in MCL cells. If identified, these features may be used as molecular targets for the effective elimination of TRAIL-resistant lymphoma cells. From an established TRAIL-sensitive mantle cell lymphoma cell line (HBL-2) we derived a TRAIL-resistant HBL-2/R subclone. By TRAIL receptor analysis and differential proteomic analysis of HBL-2 and HBL-2/R cells we revealed a marked downregulation of all TRAIL receptors and, among others, the decreased expression of 3 key enzymes of purine nucleotide metabolism, namely purine nucleoside phosphorylase, adenine phosphoribosyltransferase and inosine-5'-monophosphate dehydrogenase 2, in the resistant HBL-2/R cells. The downregulation of the 3 key enzymes of purine metabolism can have profound effects on nucleotide homeostasis in TRAIL-resistant lymphoma cells and can render such cells vulnerable to any further disruption of purine nucleotide metabolism. This pathway represents a 'weakness' of the TRAIL-resistant MCL cells and has potential as a therapeutic target for the selective elimination of such cells.

• MeSH
• 2D gelová elektroforéza MeSH
• buněčná membrána metabolismus   MeSH
• buněčná smrt účinky léků   MeSH
• chemorezistence účinky léků   MeSH
• lidé MeSH
• lymfom z plášťových buněk enzymologie   patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny metabolismus   MeSH
• protein TRAIL farmakologie   MeSH
• proteomika MeSH
• průtoková cytometrie MeSH
• puriny metabolismus   MeSH
• reprodukovatelnost výsledků MeSH
• TRAIL receptory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cathepsin D (CD), a ubiquitously expressed lysosomal aspartic protease, is upregulated in human breast carcinoma and many other tumor types. CD has been repeatedly reported to act as key mediator of apoptosis induced by various chemotherapeutics. However, there is still controversy over the role of enzymatic/proteolytic versus protein-protein interaction activities of CD in apoptotic signaling. The elucidation of molecular mechanism responsible for the effect of CD in the chemotherapy-induced cell death is crucial for development of an appropriate strategy to target this protease in cancer treatment. Therefore, the objective of this study was to investigate the molecular mechanism behind the CD-mediated regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. For this purpose, MDA-MB-231 breast carcinoma cells with an increased level of wt CD (CD) or mutant enzymatically inactive CD (ΔCD) were subjected to TRAIL and the frequency of apoptosis was determined. Our results show that CD facilitates the TRAIL-induced apoptosis of MDA-MB-231 breast cancer cells in enzymatic activity-dependent manner. Moreover, the importance of endosomal/lysosomal acidification in this process was documented. Analysis of the potential substrates specifically cleaved by CD during the TRAIL-induced apoptosis confirmed caspase-8 and Bid proteins as the CD targets. Moreover, in search for protein regulators of apoptosis that can be cleaved by CD at physiologically relevant pH, we identified the Bcl-2 protein as a suitable candidate. The modulatory role of CD in cell response to TRAIL was also confirmed in another breast cancer cell line SKBR3. These experiments identified the CD enzymatic activity as a new factor affecting sensitivity of breast cancer cells to TRAIL.

• MeSH
• adenokarcinom enzymologie   patologie   MeSH
• aktivace enzymů MeSH
• apoptóza účinky léků   MeSH
• chemorezistence MeSH
• endozomy metabolismus   MeSH
• kaspasa 8 metabolismus   MeSH
• kathepsin D antagonisté a inhibitory   genetika   fyziologie   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• malá interferující RNA genetika   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny antagonisté a inhibitory   genetika   fyziologie   MeSH
• nádory prsu enzymologie   patologie   MeSH
• protein Bid metabolismus   MeSH
• protein TRAIL farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• rekombinantní proteiny metabolismus   farmakologie   MeSH
• RNA interference MeSH
• transfekce MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• Klíčová slova
• Enbrel,
• MeSH
• beta-talasemie farmakoterapie   komplikace   terapie   MeSH
• etanercept MeSH
• imunoglobulin E terapeutické užití   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• psoriáza farmakoterapie   komplikace   terapie   MeSH
• TNF decoy receptory terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• biologická terapie * ekonomika   metody   MeSH
• dospělí MeSH
• imunoglobulin G aplikace a dávkování   MeSH
• kvalita života * MeSH
• lidé MeSH
• náklady na léky * statistika a číselné údaje   MeSH
• psoriáza * ekonomika   farmakoterapie   MeSH
• receptory faktorů nádorové nekrózy - člen 10c aplikace a dávkování   MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Mantle cell lymphoma (MCL) is incurable B-cell non-Hodgkin lymphoma and thus improving an outcome of MCL patients with new treatment options is of great importance. We plan to evaluate impact of experimental combinatorial approaches on MCL cell lines both in vitro and in vivo (xenotransplants into immunodeficient mice) via targeting the MCL-associated aberrant molecular events by new generation of cytotoxic agents, e.g. roscovitine, gemcitabine or temsirolimus, and the death-receptor pathway by the proapoptotic cytokine TRAIL. We presuppose to identify novel TRAIL "sensitizers" among the new-generation anti-lymphoma drugs. We expect to elucidate yet undescribed molecular mechanisms, by which such sensitizers augment proapoptotic effects of the recombinant TRAIL. The results of this proposed project may have important implications for the therapy of mantle cell lymphoma and will provide substantiation for design of novel combinatorial approaches that may grant or prolong survival of MCL patients.

Lymfom z plášťových buněk (MCL) je nevyléčitelná forma B-nehodgkinského lymfomu (B-NHL). Vývoj a preklinické testování nových protilymfomových léků / léčebných strategií představuje proto zásadní prioritu. Cílem předkládaného projektu je vyhodnotit efektexperimentálních terapeutických postupů kombinujících cílený zásah do deregulovaných molekul / signálních drah nově zaváděnými protilymfomovými cytostatiky (např. bortezomib, temsirolimus, roscovitine) a indukci receptorové apoptotické dráhy proapoptotickým ligandem TRAILem. Experimenty budou prováděny in vitro na MCL buněčných liniích a in vivo na myším modelu lidského MCL (systémová xenotransplantace). Předpokládáme, že identifikujeme cytostatika, která budou vykazovat synergistický cytotoxický účinek s TRAILem. Očekáváme, že se nám podaří objasnit molekulární podstatu látkového synergismu. Výsledky studie mohou mít zásadní dopad na vytváření nových, klinicky účinnějších terapeutických postupů v léčbě lymfomu z plášťových buněk u člověka.

• MeSH
• apoptóza MeSH
• cytostatické látky MeSH
• experimentální terapie MeSH
• Jurkat buňky MeSH
• kaspasa 10 MeSH
• lymfom z plášťových buněk terapie   MeSH
• modely u zvířat MeSH
• myši MeSH
• nehodgkinský lymfom terapie   MeSH
• protein TRAIL MeSH
• synergismus léků MeSH
• transplantace heterologní MeSH
• Check Tag
• myši MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hematologie a transfuzní lékařství
• onkologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

BACKGROUND: Dulanermin-a non-polyhistidine-tagged soluble recombinant human apoptosis ligand 2 (Apo2L) or tumour-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-has pro-apoptotic activity in a range of cancers and synergistic preclinical activity with rituximab against lymphoma in vivo. We aimed to assess the safety, pharmacokinetics, and efficacy of dulanermin and rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma. METHODS: We did an open-label phase 1b/2 randomised study. Four study centres in the USA enrolled patients into phase 1b, and 27 study centres in the USA, Italy, Australia, France, Czech Republic, New Zealand, and Poland enrolled patients into phase 2. In phase 1b, patients (age ≥18 years) with indolent B-cell non-Hodgkin lymphoma with stable disease or better lasting at least 6 months after the most recent rituximab-containing regimen were included. In phase 2, patients (age ≥18 years) with follicular lymphoma grades 1-3a were included. In phase 1b, patients received 4 mg/kg or 8 mg/kg intravenous dulanermin on days 1-5 of up to four 21-day cycles and intravenous rituximab 375 mg/m(2) weekly for up to eight doses. In phase 2, patients were randomly assigned (1:1:1) centrally by an interactive voice response system to dulanermin (8 mg/kg for a maximum of four 21-day cycles), rituximab (375 mg/m(2) weekly for up to eight doses), or both in combination, stratified by baseline follicular lymphoma International Prognostic Index (0-3 vs 4-5) and geographic site (USA vs non-USA). The primary endpoints of the phase 1b study were the safety, tolerability, and pharmacokinetics of dulanermin with rituximab. The primary endpoint of phase 2 was the proportion of patients who achieved an objective response. All patients who received any dose of study drug were included in safety analyses. Efficacy analyses were per protocol. Treatment was open label; all patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, NCT00400764. FINDINGS: Between June 6, 2006, and Feb 15, 2007, 12 patients were enrolled in phase 1b, and between April 4, 2007, and April 20, 2009, 60 patients were enrolled in phase 2, of whom 59 were included in safety analyses and 58 in efficacy analyses. No dose-limiting toxic effects were noted in phase 1b. The most common grade 1-2 adverse events in phase 1b were fatigue (nine; 75%), rash (five; 42%), and chills, decreased appetite, diarrhoea, and nausea (four each; 33%). 19 grade 3 or higher adverse effects were noted in five (42%) patients, with 14 occurring in one patient. After treatment with 8 mg/kg of dulanermin, in six patients the mean serum peak concentration was 80 μg/mL, dropping below the minimum detectable concentration (2 ng/mL) within 24 h after the dose. The mean steady state peak and trough concentrations of rituximab were 461 μg/mL (SD 97.5) and 303 μg/mL (92.8), respectively. In phase 2, eight (14%) of 59 patients experienced 12 grade 3 or higher adverse events. In phase 2, objective responses were noted in 14 of 22 (63.6%, 95% CI 41.8-81.3) patients treated with rituximab only, 16 of 25 (64.0%, 43.1-81.5) treated with dulanermin and rituximab, and one of 11 (9.1%, 0.5-39.0) treated with dulanermin only. The study was terminated early, on May 5, 2010, because of an absence of efficacy in the combination group. INTERPRETATION: The addition of dulanermin to rituximab in patients with indolent B-cell non-Hodgkin lymphoma was tolerable but did not lead to increased objective responses. This combination is not being developed further in non-Hodgkin lymphoma. FUNDING: Genentech and Amgen.

• MeSH
• B-buněčný lymfom farmakoterapie   MeSH
• folikulární lymfom farmakoterapie   MeSH
• lidé MeSH
• protein TRAIL terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• rituximab terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé 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
• Geografické názvy
• Austrálie MeSH
• Česká republika MeSH
• Francie MeSH
• Itálie MeSH
• Nový Zéland MeSH
• Polsko MeSH
• Spojené státy americké MeSH

Článek si klade za úkol seznámit čtenáře s postavením a využitím biologické léčby u vybraných revmatických onemocnění. Prudký rozvoj biologické terapie v posledních dvou dekádách a její zavedení do klinické praxe výrazně zlepšilo prognózu nemocných s velmi aktivní revmatoidní, či psoriatickou artritidou a ankylozující spondylitidou, u kterých došlo k selhání podávané konvenční terapie. Autoři se zabývají vybranými skupinami biologických léků, jejich indikacemi, monitorací účinnosti, nežádoucími účinky a některými úskalími využití těchto léků.

The goal of this short review is to inform readers about the position and utilization of biological agents in therapy of selected rheumatic disorders. The advancement of biological agents in last two decades and their introduction in clinical practice led to prognosis improvement in very active rheumatoid and psoriatic arthritis and ankylosing spondylitis patients, who did not respond to conventional therapy. The authors discuss the selected biological agents – their indications, the follow up of their effects, the adverse events and pitfalls of their usage.

• Klíčová slova
• anti-TNF? terapie, biologická léčba, golimumab, tocilizumab, anakinra,
• MeSH
• abatacept MeSH
• adalimumab MeSH
• ankylózující spondylitida farmakoterapie   MeSH
• biologická terapie škodlivé účinky   trendy   využití   MeSH
• certolizumab pegol MeSH
• etanercept MeSH
• imunoglobulin G aplikace a dávkování   terapeutické užití   MeSH
• imunoglobuliny - Fab fragmenty aplikace a dávkování   terapeutické užití   MeSH
• imunokonjugáty aplikace a dávkování   terapeutické užití   MeSH
• infliximab MeSH
• lidé MeSH
• monoklonální protilátky aplikace a dávkování   terapeutické užití   MeSH
• polyethylenglykoly aplikace a dávkování   terapeutické užití   MeSH
• psoriatická artritida farmakoterapie   MeSH
• receptory faktorů nádorové nekrózy - člen 10c aplikace a dávkování   terapeutické užití   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• rituximab MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH