Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 μM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.

• MeSH
• apoptóza * účinky léků   MeSH
• bcr-abl fúzní proteiny * genetika   antagonisté a inhibitory   metabolismus   MeSH
• chemorezistence * účinky léků   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   patologie   MeSH
• dasatinib farmakologie   MeSH
• imatinib mesylát * farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas * farmakologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• oligonukleotidy * farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.

• MeSH
• cisplatina * farmakologie   MeSH
• dasatinib * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny farmakologie   chemie   chemická syntéza   MeSH
• prekurzory léčiv * farmakologie   chemie   chemická syntéza   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• synergismus léků * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.

• MeSH
• aplikace orální MeSH
• biologická dostupnost MeSH
• dasatinib MeSH
• klinické křížové studie MeSH
• lidé MeSH
• omeprazol * farmakokinetika   MeSH
• plocha pod křivkou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• nilotinib, bosutinib, ponatinib,
• MeSH
• aniliny aplikace a dávkování   terapeutické užití   MeSH
• chinoliny aplikace a dávkování   terapeutické užití   MeSH
• chronická fáze myeloidní leukemie terapie   MeSH
• chronická myeloidní leukemie * terapie   MeSH
• dasatinib aplikace a dávkování   terapeutické užití   MeSH
• imatinib mesylát aplikace a dávkování   terapeutické užití   MeSH
• imidazoly aplikace a dávkování   terapeutické užití   MeSH
• inhibitory proteinkinas aplikace a dávkování   terapeutické užití   MeSH
• inhibitory tyrosinkinasy aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• nemoc štěpu proti hostiteli MeSH
• nitrily aplikace a dávkování   terapeutické užití   MeSH
• pyridaziny aplikace a dávkování   terapeutické užití   MeSH
• pyrimidiny aplikace a dávkování   terapeutické užití   MeSH
• retrospektivní studie MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• Check Tag
• lidé MeSH

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL oncogene. Despite the high performance of treatment with tyrosine kinase inhibitors (TKI), about 30% of patients develop resistance to the therapy. To improve the outcomes, identification of new targets of treatment is needed. Here, we explored the Casein Kinase 2 (CK2) as a potential target for CML therapy. Previously, we detected increased phosphorylation of HSP90β Serine 226 in patients non-responding to TKIs imatinib and dasatinib. This site is known to be phosphorylated by CK2, which was also linked to CML resistance to imatinib. In the present work, we established six novel imatinib- and dasatinib-resistant CML cell lines, all of which had increased CK2 activation. A CK2 inhibitor, CX-4945, induced cell death of CML cells in both parental and resistant cell lines. In some cases, CK2 inhibition also potentiated the effects of TKI on the cell metabolic activity. No effects of CK2 inhibition were observed in normal mononuclear blood cells from healthy donors and BCR-ABL negative HL60 cell line. Our data indicate that CK2 kinase supports CML cell viability even in cells with different mechanisms of resistance to TKI, and thus represents a potential target for treatment.

• MeSH
• apoptóza MeSH
• bcr-abl fúzní proteiny metabolismus   MeSH
• buněčná smrt MeSH
• chemorezistence MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• dasatinib farmakologie   MeSH
• imatinib mesylát farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• inhibitory tyrosinkinasy MeSH
• kaseinkinasa II * MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

• MeSH
• dasatinib MeSH
• endoteliální buňky * metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• neutrofily metabolismus   MeSH
• skupina kinas odvozených od src-genu * genetika   metabolismus   MeSH
• vaskulitida * genetika   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The treatment outcome in patients with chronic myeloid leukaemia (CML) in blast crisis (BC) is unsatisfactory despite the use of allogeneic stem cell transplantation (ASCT). Moreover, in some patients ASCT is contraindicated, with limited treatment options. We report the case series of two patients with lymphoid BC CML in whom ASCT was not approachable. The first patient developed BC two months after diagnosis in association with dic(7;9)(p11.2;p11.2) and T315I mutation. Blast crisis with central nervous system leukemic involvement and K611N mutation of the SETD2 gene developed abruptly in the second patient five years after ceasing treatment with nilotinib in major molecular response (MMR) at the patient's request. Both underwent one course of chemotherapy in combination with rituximab and imatinib, followed by dasatinib and interferon α (INFα) treatment in the first and dasatinib alone in the second case. Deep molecular response (DMR; MR 4.0) was achieved within a short time in both cases. It is probable that DMR was caused by a specific immune response to CML cells, described in both agents. The challenging medical condition that prompted these case series, and the subsequent results, suggest a re-visit to the use of a combination of well-known drugs as an area for further investigation.

• MeSH
• blastická krize * farmakoterapie   genetika   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   MeSH
• dasatinib terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• interferon alfa terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• kazuistiky MeSH

Léky vyvolané perikarditidy nejsou časté, ale závažné onemocnění, protože případná tamponáda perikardu může ohrozit život pacienta. Vzhledem k tomu, že nabídka nových léků se neustále rozšiřuje, zvyšuje se i podíl léčiv schopných perikarditidu vyvolat. Autoři vyhodnotili práce s touto tematikou uvedené v databázi PubMed a doplnili informacemi z databáze VigiBase. Ve svém článku autoři uvádějí současné poznatky o mechanismech vzniku i stupni rizika vzniku léky vyvolané perikarditidy. Uvádějí relevantní informace o jednotlivých lécích rozdělených do sedmi skupin. U některých léčiv je riziko vzniku perikarditidy vysoké a při léčbě těmito přípravky je nutné toto riziko brát v úvahu.

Though not common, drug-induced pericarditis is a serious condition, since pericardial tamponade, should it develop, may be life-threatening. As the number of drugs is constantly expanding, so does the proportion of those capable of causing pericarditis. The authors reviewed the relevant literature in the PubMed database and complemented it with information from the VigiBase database. In their article, the authors present current knowledge about the mechanisms of origin and level of risk of drug-induced pericarditis and discuss relevant information on individual drugs divided into 7 classes. Some medicines are associated with a high risk of developing pericarditis, a fact to be taken into account when treating patients with these agents.

• Klíčová slova
• ceritinib,
• MeSH
• dasatinib škodlivé účinky   toxicita   MeSH
• inhibitory proteinkinas škodlivé účinky   toxicita   MeSH
• klozapin škodlivé účinky   toxicita   MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• pentostatin škodlivé účinky   toxicita   MeSH
• perikarditida * chemicky indukované   MeSH
• sulfasalazin škodlivé účinky   toxicita   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

To evaluate long-term real-life results of dasatinib therapy among chronic phase chronic myeloid leukemia patients resistant or intolerant to imatinib, we retrospectively analyzed data of 118 patients treated in centers participating in the database INFINITY. With median follow-up of 37 months, estimated 5-year cumulative incidences of complete cytogenetic and major molecular responses were 78% and 68%, respectively. The estimated 5-year probability of overall survival (OS) and event-free survival (EFS) were 86% and 83%, respectively. Both OS and EFS were significantly improved among patients with BCR-ABL1 transcript level ≤10% at 3 months. Dasatinib toxicity was tolerable however persistent in almost half our patients, even after years of therapy. Pleural effusion occurred in 29% of patients and was responsible for 30% of dasatinib discontinuations. Our results confirmed very good efficacy and acceptable toxicity of dasatinib in second line setting and support the evidence and importance of high-quality real-life CML patient management.

• MeSH
• chronická fáze myeloidní leukemie * farmakoterapie   genetika   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   MeSH
• dasatinib škodlivé účinky   MeSH
• imatinib mesylát škodlivé účinky   MeSH
• inhibitory proteinkinas škodlivé účinky   MeSH
• lidé MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Bcr-Abl tyrosine kinase inhibitors significantly improved Philadelphia chromosome-positive leukaemia therapy. Apart from Bcr-Abl kinase, imatinib, dasatinib, nilotinib, bosutinib and ponatinib are known to have additional off-target effects that might contribute to their antitumoural activities. In our study, we identified aldo-keto reductase 1B10 (AKR1B10) as a novel target for dasatinib. The enzyme AKR1B10 is upregulated in several cancers and influences the metabolism of chemotherapy drugs, including anthracyclines. AKR1B10 reduces anthracyclines to alcohol metabolites that show less antineoplastic properties and tend to accumulate in cardiac tissue. In our experiments, clinically achievable concentrations of dasatinib selectively inhibited AKR1B10 both in experiments with recombinant enzyme (Ki = 0.6 µM) and in a cellular model (IC50 = 0.5 µM). Subsequently, the ability of dasatinib to attenuate AKR1B10-mediated daunorubicin (Daun) resistance was determined in AKR1B10-overexpressing cells. We have demonstrated that dasatinib can synergize with Daun in human cancer cells and enhance its therapeutic effectiveness. Taken together, our results provide new information on how dasatinib may act beyond targeting Bcr-Abl kinase, which may help to design new chemotherapy regimens, including those with anthracyclines.

• MeSH
• aldo-keto reduktasy antagonisté a inhibitory   chemie   metabolismus   MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   chemie   metabolismus   MeSH
• buňky A549 MeSH
• chemorezistence účinky léků   fyziologie   MeSH
• dasatinib aplikace a dávkování   MeSH
• daunomycin aplikace a dávkování   MeSH
• HCT116 buňky MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• lékové transportní systémy metody   MeSH
• lidé MeSH
• protinádorové látky aplikace a dávkování   MeSH
• sekundární struktura proteinů MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH