Článek se zabývá problematikou léčby II. linie metastatického BRAF-mutovaného maligního melanomu v situaci, kdy jsou k dispozici nové léčebné možnosti jako inhibitory BRAF a anti-PD-1 protilátky. Případ popsaný v článku pak popisuje praktickou zkušenost s léčebnou sekvencí vemurafenib/pembrolizumab.
Actually we have two challenging treatment options for treatment of metastatic BRAF-mutated malignant melanoma. These are BRAF inhibitors and anti-PD-1 antibodies. Here we present a clinical case of treatment sequence vemurafenib/pembrolizumab.
- Klíčová slova
- Zelboraf (vemurafenib - serin-threonin kináza), Keytruda (permolizumab - humanizovaná IgG4 monoklonální protilátka proti PD-1),
- MeSH
- hodnocení léčiv * MeSH
- humanizované monoklonální protilátky aplikace a dávkování terapeutické užití MeSH
- imunoglobulin G MeSH
- klinický obraz nemoci MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody využití MeSH
- melanom * diagnóza farmakoterapie klasifikace MeSH
- metastázy nádorů * diagnóza farmakoterapie MeSH
- PET/CT metody využití MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory aplikace a dávkování účinky léků MeSH
- protoonkogenní proteiny B-raf genetika účinky léků MeSH
- senioři MeSH
- statistika jako téma MeSH
- výsledky a postupy - zhodnocení (zdravotní péče) MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
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
Human checkpoint kinase 1 (Chk1) is an essential kinase required to preserve genome stability. Here, we show that Chk1 inhibition by two distinct drugs, UCN-01 and CEP-3891, or by Chk1 small interfering RNA (siRNA) leads to phosphorylation of ATR targets. Chk1-inhibition triggered rapid, pan-nuclear phosphorylation of histone H2AX, p53, Smc1, replication protein A, and Chk1 itself in human S-phase cells. These phosphorylations were inhibited by ATR siRNA and caffeine, but they occurred independently of ATM. Chk1 inhibition also caused an increased initiation of DNA replication, which was accompanied by increased amounts of nonextractable RPA protein, formation of single-stranded DNA, and induction of DNA strand breaks. Moreover, these responses were prevented by siRNA-mediated downregulation of Cdk2 or the replication initiation protein Cdc45, or by addition of the CDK inhibitor roscovitine. We propose that Chk1 is required during normal S phase to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. These results may help explain why Chk1 is an essential kinase and should be taken into account when drugs to inhibit this kinase are considered for use in cancer treatment.
- MeSH
- ATM protein MeSH
- checkpoint kinasa 2 MeSH
- chromozomální proteiny, nehistonové metabolismus MeSH
- DNA vazebné proteiny metabolismus MeSH
- fosforylace MeSH
- histony metabolismus MeSH
- inhibitory proteinkinas farmakologie MeSH
- jednovláknová DNA metabolismus MeSH
- kofein farmakologie MeSH
- lidé MeSH
- malá interferující RNA farmakologie genetika MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- poškození DNA * fyziologie MeSH
- protein-serin-threoninkinasy fyziologie účinky léků MeSH
- proteinkinasy farmakologie fyziologie genetika MeSH
- proteiny buněčného cyklu fyziologie genetika metabolismus MeSH
- puriny farmakologie MeSH
- replikace DNA fyziologie účinky léků MeSH
- replikační protein A MeSH
- staurosporin * analogy a deriváty farmakologie MeSH
- Check Tag
- lidé MeSH
