Overactivation of Src has been linked to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). This phase 2, multisite study assessed the efficacy and safety of bosutinib, an oral dual Src/Bcr-Abl tyrosine kinase inhibitor, in patients with ADPKD. Patients with ADPKD, eGFR≥60 ml/min per 1.73 m2, and total kidney volume ≥750 ml were randomized 1:1:1 to bosutinib 200 mg/d, bosutinib 400 mg/d, or placebo for ≤24 months. The primary endpoint was annualized rate of kidney enlargement in patients treated for ≥2 weeks who had at least one postbaseline magnetic resonance imaging scan that was preceded by a 30-day washout (modified intent-to-treat population). Of 172 enrolled patients, 169 received at least one study dose. Per protocol amendment, doses for 24 patients who initially received bosutinib at 400 mg/d were later reduced to 200 mg/d. The annual rate of kidney enlargement was reduced by 66% for bosutinib 200 mg/d versus placebo (1.63% versus 4.74%, respectively; P=0.01) and by 82% for pooled bosutinib versus placebo (0.84% versus 4.74%, respectively; P<0.001). Over the treatment period, patients receiving placebo or bosutinib had similar annualized eGFR decline. Gastrointestinal and liver-related adverse events were the most frequent toxicities. In conclusion, compared with placebo, bosutinib at 200 mg/d reduced kidney growth in patients with ADPKD. The overall gastrointestinal and liver toxicity profile was consistent with the profile in prior studies of bosutinib; no new toxicities were identified. (ClinicalTrials.gov: NCT01233869).

• Klíčová slova
• ADPKD, Src, bosutinib, clinical trial, total kidney volume,
• MeSH
• aniliny škodlivé účinky   terapeutické užití   MeSH
• chinoliny škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nitrily škodlivé účinky   terapeutické užití   MeSH
• polycystické ledviny autozomálně dominantní farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• aniliny MeSH
• bosutinib MeSH Prohlížeč
• chinoliny MeSH
• nitrily MeSH

Potentiometric and spectrophotometric pH-titration of the multiprotic cytostatics bosutinib for dissociation constants determination were compared. Bosutinib treats patients with positive chronic myeloid leukemia. Bosutinib exhibits four protonatable sites in a pH range from 2 to 11, where two pK are well separated (ΔpK>3), while the other two are near dissociation constants. In the neutral medium, bosutinib occurs in the slightly water soluble form LH that can be protonated to the soluble cation LH4(3+). The molecule LH can be dissociated to still difficultly soluble anion L(-). The set of spectra upon pH from 2 to 11 in the 239.3-375.0nm was divided into two absorption bands: the first one from 239.3 to 290.5nm and the second from 312.3 to 375.0nm, which differ in sensitivity of chromophores to a pH change. Estimates of pK of the entire set of spectra were compared with those of both absorption bands. Due to limited solubility of bosutinib the protonation in a mixed aqueous-methanolic medium was studied. In low methanol content of 3-6% three dissociation constants can be reliably determined with SPECFIT/32 and SQUAD(84) and after extrapolation to zero content of methanol they lead to pKc1=3.43(12), pKc2=4.54(10), pKc3=7.56(07) and pKc4=11.04(05) at 25°C and pKc1=3.44(06), pKc2=5.03(08) pKc3=7.33(05) and pKc4=10.92(06) at 37°C. With an increasing content of methanol in solvent the dissociation of bosutinib is suppressed and the percentage of LH3(2+) decreases and LH prevails. From the potentiometric pH-titration at 25°C the concentration dissociation constants were estimated with ESAB pKc1=3.51(02), pKc2=4.37(02), pKc3=7.97(02) and pKc4=11.05(03) and with HYPERQUAD: pKc1=3.29(12), pKc2=4.24(10), pKc3=7.95(07) and pKc4=11.29(05).

• Klíčová slova
• Bosutinib, Dissociation constants, ESAB2M, HYPERQUAD, INDICES, PALLAS, Potentiometric Titration, SQUAD(84) SPECFIT/32, Spectrophotometric titration,
• MeSH
• aniliny analýza   chemie   MeSH
• chinoliny analýza   chemie   MeSH
• cytostatické látky analýza   chemie   MeSH
• koncentrace vodíkových iontů MeSH
• metoda nejmenších čtverců MeSH
• nelineární dynamika * MeSH
• nitrily analýza   chemie   MeSH
• potenciometrie MeSH
• spektrofotometrie metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aniliny MeSH
• bosutinib MeSH Prohlížeč
• chinoliny MeSH
• cytostatické látky MeSH
• nitrily MeSH

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia that is characterised by Philadelphia chromosome (Ph1 chromosome) and/or fusion gene BCR-ABL1 in bone marrow. Interpheron α and bone marrow transplantation used to be the main treatment modalities for patients with CML 20 years ago. Due to the introduction of imatinib mesylate since the year 2000 the outcome of CML patients has dramatically improved. The survival of both younger and elderly patients in the case of an optimal response has been prolonged and currently is close to survival of healthy population. Although, one third of patients does not respond well to first line imatinib and needs to change the treatment to second line tyrosine kinase inhibitors (TKI: bosutinib, dasatinib and nilotinib). Younger patients without cardiologic and metabolic disorders and those with poor risk profile score may have benefit from TKI of 2nd generation as a 1st line treatment option with the aim of reaching deeper molecular response and the chance of treatment free remission (TFR) in future. By older patients with severe comorbidities and in patients with good risk profile score imatinib as a 1st line treatment option can be used. For patients who are resistant simultaneously to 2nd generation TKI and for patients with mutation T315I ponatinib - TKI of 3rd generation can be used effectively. Intolerance and toxicity of TKI´s are the main barriers of effective CML treatment. TKI selection for each patient should be individual. Patient´s cooperation with medical team is crucial and inevitable in long time treatment process. The chance for TFR has become feasible for approximately 40-60 % CML patients in deep and durable molecular remission and represents a further important milestone in the management of CML patients.

• Klíčová slova
• bosutinib, chronic myeloid leukemia, dasatinib, hematopoietic stem cell transplantation, imatinib, nilotinib, ponatinib, remission, tyrosine kinase inhibitors,
• MeSH
• antitumorózní látky * terapeutické užití   MeSH
• bcr-abl fúzové proteiny genetika   terapeutické užití   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   MeSH
• dasatinib terapeutické užití   MeSH
• dospělí MeSH
• imatinib mesylát terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky * MeSH
• bcr-abl fúzové proteiny MeSH
• dasatinib MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH

While targeted therapy based on the idea of attenuating the activity of a preselected, therapeutically relevant protein has become one of the major trends in modern cancer therapy, no truly specific targeted drug has been developed and most clinical agents have displayed a degree of polypharmacology. Therefore, the specificity of anticancer therapeutics has emerged as a highly important but severely underestimated issue. Chemical proteomics is a powerful technique combining postgenomic drug-affinity chromatography with high-end mass spectrometry analysis and bioinformatic data processing to assemble a target profile of a desired therapeutic molecule. Due to high demands on the starting material, however, chemical proteomic studies have been mostly limited to cancer cell lines. Herein, we report a down-scaling of the technique to enable the analysis of very low abundance samples, as those obtained from needle biopsies. By a systematic investigation of several important parameters in pull-downs with the multikinase inhibitor bosutinib, the standard experimental protocol was optimized to 100 μg protein input. At this level, more than 30 well-known targets were detected per single pull-down replicate with high reproducibility. Moreover, as presented by the comprehensive target profile obtained from miniaturized pull-downs with another clinical drug, dasatinib, the optimized protocol seems to be extendable to other drugs of interest. Sixty distinct human and murine targets were finally identified for bosutinib and dasatinib in chemical proteomic experiments utilizing core needle biopsy samples from xenotransplants derived from patient tumor tissue. Altogether, the developed methodology proves robust and generic and holds many promises for the field of personalized health care.

• MeSH
• aniliny chemie   MeSH
• anotace sekvence MeSH
• biopsie MeSH
• buňky K562 MeSH
• chinoliny chemie   MeSH
• chromatografie afinitní MeSH
• cílená molekulární terapie MeSH
• dasatinib MeSH
• inhibitory proteinkinas chemie   MeSH
• lidé MeSH
• mapy interakcí proteinů MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• nádory plic farmakoterapie   enzymologie   patologie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   enzymologie   patologie   MeSH
• nitrily chemie   MeSH
• proteomika MeSH
• pyrimidiny chemie   MeSH
• thiazoly chemie   MeSH
• transplantace nádorů MeSH
• tyrosinkinasy izolace a purifikace   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• aniliny MeSH
• bosutinib MeSH Prohlížeč
• chinoliny MeSH
• dasatinib MeSH
• inhibitory proteinkinas MeSH
• nitrily MeSH
• pyrimidiny MeSH
• thiazoly MeSH
• tyrosinkinasy MeSH

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

• MeSH
• analýza přežití MeSH
• aniliny terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• bcr-abl fúzové proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• chinoliny terapeutické užití   MeSH
• chronická myeloidní leukemie diagnóza   farmakoterapie   genetika   mortalita   MeSH
• dasatinib terapeutické užití   MeSH
• exprese genu MeSH
• imatinib mesylát terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• klinické rozhodování MeSH
• konsensuální konference jako téma MeSH
• kvalita života MeSH
• lidé MeSH
• management nemoci MeSH
• monitorování fyziologických funkcí MeSH
• naděje dožití trendy   MeSH
• nitrily terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• aniliny MeSH
• antitumorózní látky MeSH
• bcr-abl fúzové proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• bosutinib MeSH Prohlížeč
• chinoliny MeSH
• dasatinib MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• nilotinib MeSH Prohlížeč
• nitrily MeSH
• pyrimidiny 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.

• Klíčová slova
• Anthracyclines, Cancer therapy, Leukaemia, Multidrug resistance, Reductase,
• MeSH
• aldo-keto reduktasy antagonisté a inhibitory   chemie   metabolismus   MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• bcr-abl fúzové 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
• lidé MeSH
• sekundární struktura proteinů MeSH
• simulace molekulového dockingu MeSH
• systémy cílené aplikace léků metody   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AKR1B10 protein, human MeSH Prohlížeč
• aldo-keto reduktasy MeSH
• antitumorózní látky MeSH
• bcr-abl fúzové proteiny MeSH
• dasatinib MeSH
• daunomycin MeSH
• inhibitory proteinkinas MeSH

Capillary electrophoresis connected with tandem mass spectrometry was employed for the development of a method for determination of various tyrosine kinase inhibitors in plasma samples. A stacking online preconcentration with a 120 cm-long capillary was used for the determination of bosutinib, dasatinib, canertinib, and erlotinib at physiologically relevant concentrations. The optimization included both capillary electrophoresis and mass spectrometry steps. Under optimal conditions, 50 mM formic acid pH 2.5, an injection time of 120 s, and an optimized mass spectrometry set-up (as sheath liquid composition 75:24.9:0.1 (v/v) methanol, water, formic acid, and appropriate conditions for ion transitions), LODs in a range of 3.9-23.0 nmol·L-1 were observed. The method was validated in terms of linearity, limit of detection, limit of quantification, repeatability of migration times and peak area, and recovery using plasma as a matrix for analytes. The results showed that this method has great promise for use in many analytical tasks, e.g., therapeutic drug monitoring.

• Klíčová slova
• capillary electrophoresis, mass spectrometry, online preconcentration, stacking, tyrosine kinase inhibitors,
• Publikační typ
• časopisecké články MeSH