Among novel promising approaches to anticancer therapy belongs the targeting inhibition of signal transduction. This review outlines present-day experiences with imatinib (Glivec), a potent inhibitor of the tyrosine kinases bcr-abl, c-kit and platelet-derived growth factor receptor kinase. Due to inhibition of bcr-abl tyroxine kinase, imatinib has rapidly become the standard therapy for chronic myelocytic leukemia; inhibition of c-kit receptor explains its effectivity in the treatment of patients with gastrointestinal stromal tumors. Another known target of imatinib is tyrosine kinase of PDGFR, which is activated in numerous malignancies, particularly in dermatofibrosarcoma protuberans. Discovery of the novel fusion gene in hypereosinophilic syndrome (FIPILI-PFGFRA, whose product is an imatinib sensitive protein kinase) permitted to treat successfully this event. Possible combination of imatinib with conventional chemotherapeutic drugs and other key signal transduction inhibitors are mentioned.

• MeSH
• benzamidy MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• gastrointestinální stromální tumory farmakoterapie   MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• piperaziny chemie   farmakologie   terapeutické užití   MeSH
• protinádorové látky chemie   farmakologie   terapeutické užití   MeSH
• pyrimidiny chemie   farmakologie   terapeutické užití   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• benzamidy MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH
• tyrosinkinasy MeSH

The new knowledge in molecular biology and pathophysiology of chronic myeloid leukemia enabled the development of imatinib mesylate (Glivec, formerly STI571). Imatinib potently inhibits several protein tyrosine kinases, including BCR-ABL, c-Kit, and PDGF receptor. Imatinib blocks the phosphorylation of downstream target proteins and interrupts the malignant transformation leading to the development of CML. Phase I and II studies demonstrated that imatinib is highly effective and well tolerated in all phase of CML. We got our experience with imatinib on more than two-year monitoring 34 patients within the Expanded Access Study CST1571 0113. Imatinib 400 mg/d was administered orally to 10 women and 24 men in median age of 53 years (22-70) who were hematologically (n = 9) or cytogenetically (n = 13) resistant, cytogenetically refractory (n = 3) or intolerant (n = 9) to interferon alpha. The median follow-up time was 97.5 weeks (23-115), the median time from CML diagnosis to the start of the study was 32.3 months (6-140.5). Complete hematologic response was achieved in 33 of 34 (97%) pts, total major cytogenetic response (complete plus major) in 21 of 33 (63%) pts. Cytogenetic relapse was observed in 2 of 33 pts (6%), cytogenetic progression in 4 (12%) pts. Non-hematologic toxicity was mild (grade 1 or 2) and no patient was excluded from the study due to it. Hematological toxicity grade 3 limited dose of imatinib in 26% of patients and probably caused lower rate of cytogenetic responses in heavy pretreated patients. Both quantitative RT-PCR methods (competitive RT-PCR and real-time RT-PCR Light-Cycler) were found useful to monitor patients with CML on imatinib therapy. Our results confirmed high efficacy and safety of imatinib in late-chronic phase CML patients failing prior interferon therapy. The lower incidence of hematological toxicity and higher rate of cytogenetic responses in patients treated with imatinib in early-chronic phase CML justify according to our opinion the recommendation to administer imatinib early after the diagnosis of CML in patients who are not indicated for allogeneic transplantation.

• MeSH
• benzamidy MeSH
• chronická fáze myeloidní leukemie farmakoterapie   genetika   MeSH
• dospělí MeSH
• imatinib mesylát MeSH
• inhibitory enzymů škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• piperaziny škodlivé účinky   terapeutické užití   MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• pyrimidiny škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzamidy MeSH
• imatinib mesylát MeSH
• inhibitory enzymů MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH
• tyrosinkinasy MeSH

Untargeted metabolite profiling using high-resolution mass spectrometry coupled with liquid chromatography (LC-HRMS), followed by data analysis with the Compound Discoverer 2.0™ software, was used to study the metabolism of imatinib in humans with chronic myeloid leukemia. Plasma samples from control (drug-free) and patient (treated with imatinib) groups were analyzed in full-scan mode and the unknown ions occurring only in the patient group were then, as potential imatinib metabolites, subjected to multi-stage fragmentation in order to elucidate their structure. The application of an untargeted approach, as described in this study, enabled the detection of 24 novel structurally unexpected metabolites. Several sulphur-containing compounds, probably originating after the reaction of reactive intermediates of imatinib with endogenous glutathione, were found and annotated as cysteine and cystine adducts. In the proposed mechanism, the cysteine adducts were formed after the rearrangement of piperazine moiety to imidazoline. On the contrary, in vivo S-N exchange occurred in the case of the cystine adducts. In addition, N-O exchange was observed in the collision cell in the course of the fragmentation of the cystine adducts. The presence of sulphur in the cysteine and cystine conjugates was proved by means of ultra-high resolution measurements using Orbitrap Elite. The detection of metabolites derived from glutathione might improve knowledge about the disposition of imatinib towards bioactivation and help to improve understanding of the mechanism of its hepatotoxicity or nephrotoxicity in humans.

• Klíčová slova
• Compound Discoverer™, Glutathione, Imatinib, LC-HRMS, Metabolization, Untargeted metabolite profiling,
• MeSH
• chromatografie kapalinová MeSH
• cystein metabolismus   MeSH
• cystin metabolismus   MeSH
• imatinib mesylát krev   metabolismus   moč   MeSH
• inhibitory proteinkinas krev   metabolismus   moč   MeSH
• lidé MeSH
• protinádorové látky krev   metabolismus   moč   MeSH
• síra krev   metabolismus   moč   MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cystein MeSH
• cystin MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH
• síra MeSH

BACKGROUND: Recently, multiple epidemiological studies have linked imatinib with the alteration of renal function in chronic myeloid leukaemia (CML) patients. This meta-analysis aimed to summarize the impact of imatinib use on renal function in CML patients. METHODS: A systematic search was conducted on MEDLINE and Embase to identify articles assessing the impact of imatinib exposure on renal function in CML patients. The risk of bias was assessed using the Newcastle-Ottawa scale (NOS). Two authors independently performed literature-screening, risk of bias and data extraction. The risk of renal dysfunction (chronic kidney disease or acute kidney injury) among imatinib users was computed as the primary outcome of interest. The certainty of findings was assessed using the grading of recommendations assessment, development and evaluation (GRADE) criteria. RESULTS: A total of nine articles qualified for inclusion in the systematic review, of which four articles were eligible for meta-analysis. Based on the scoring on NOS, majority of the included studies were found to be of moderate risk of bias. Majority of the studies (n = 6) reported significantly (p < .05) decrease in estimated glomerular filtration rate (eGFR) after imatinib treatment. The risk of developing renal dysfunction (chronic kidney disease or acute kidney injury) was found to be significantly higher in imatinib users as compared to other tyrosine kinase inhibitor (TKI) users with a pooled relative risk of 2.70 (95% CI: 1.49-4.91). Sensitivity analysis also revealed a consistently high risk of renal dysfunction with imatinib use. GRADE criteria revealed low certainty of evidence. CONCLUSION: This meta-analysis found an increased risk of renal dysfunction in imatinib users compared to other TKI users.

• Klíčová slova
• cancer, chronic kidney disease, chronic myeloid leukaemia, imatinib, meta-analysis, tyrosine kinase inhibitors,
• MeSH
• chronická myeloidní leukemie * chemicky indukované   farmakoterapie   MeSH
• chronická nemoc MeSH
• imatinib mesylát škodlivé účinky   MeSH
• inhibitory proteinkinas škodlivé účinky   MeSH
• ledviny fyziologie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• Názvy látek
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH

A simple, sensitive, specific, and cost-effective analytical methodology was developed for the analysis of human plasma samples spiked with imatinib by CZE with on-line UV detection in the context of Therapeutic Drug Monitoring. Several analytical conditions such as the ionic strength (I) and the pH of the BGE composed of citric acid and ε-amino caproic acid were studied in regards of the presence of sodium chloride (NaCl) in plasma samples (1% m/v). Computer simulations (Simul software) were used to confirm the experimental results and to understand imatinib electrophoretic behavior in the presence of NaCl. Furthermore, the advantages of adding ACN to the sample containing NaCl to combine efficient protein precipitation and on-line CZE stacking of imatinib were demonstrated. LOD and LOQ values of 48 and 191 ng/mL were obtained from plasma sample supernatant after protein precipitation with ACN, which is much lower than mean imatinib plasma level observed for patients treated by imatinib mesylate (about 1000 ng/mL). Good linearity was obtained in the concentration range 191-5000 ng/mL (R2 > 0.997). RSD of less than 1.68% and 2.60% (n = 6) for migration times and corrected peak areas, respectively, were observed at the LOQ.

• Klíčová slova
• Acetonitrile, Imatinib, Peak splitting, Simul software, Sodium chloride,
• MeSH
• acetonitrily chemie   MeSH
• chlorid sodný chemie   MeSH
• elektroforéza kapilární metody   MeSH
• imatinib mesylát krev   MeSH
• lidé MeSH
• limita detekce MeSH
• lineární modely MeSH
• reprodukovatelnost výsledků MeSH
• software MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetonitrile MeSH Prohlížeč
• acetonitrily MeSH
• chlorid sodný MeSH
• imatinib mesylát MeSH

Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia.

• Klíčová slova
• Ph+ leukemia, generic medication, imatinib inhibitor, pediatric, tyrosine kinase,
• MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• dítě MeSH
• generika terapeutické užití   MeSH
• imatinib mesylát terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• protinádorové látky terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• generika MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH

The lysosomal sequestration of hydrophobic weak-base anticancer drugs is one proposed mechanism for the reduced availability of these drugs at target sites, resulting in a marked decrease in cytotoxicity and consequent resistance. While this subject is receiving increasing emphasis, it is so far only in laboratory experiments. Imatinib is a targeted anticancer drug used to treat chronic myeloid leukaemia (CML), gastrointestinal stromal tumours (GISTs), and a number of other malignancies. Its physicochemical properties make it a typical hydrophobic weak-base drug that accumulates in the lysosomes of tumour cells. Further laboratory studies suggest that this might significantly reduce its antitumor efficacy. However, a detailed analysis of published laboratory studies shows that lysosomal accumulation cannot be considered a clearly proven mechanism of resistance to imatinib. Second, more than 20 years of clinical experience with imatinib has revealed a number of resistance mechanisms, none of which is related to its accumulation in lysosomes. This review focuses on the analysis of salient evidence and raises a fundamental question about the significance of lysosomal sequestration of weak-base drugs in general as a possible resistance mechanism both in clinical and laboratory settings.

• Klíčová slova
• STI571, cancer, drug resistance mechanisms, hydrophobic weak-base drugs, lysosomal drug sequestration, tyrosine kinase inhibitors,
• MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• imatinib mesylát terapeutické užití   MeSH
• lidé MeSH
• lyzozomy MeSH
• protinádorové látky * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• imatinib mesylát MeSH
• protinádorové látky * MeSH

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by an abnormal fusion gene BCR-ABL. BCR-ABL encodes a constitutively active Bcr-Abl tyrosine kinase, which is required and sufficient for cellular transformation. Bcr-Abl is, therefore, an ideal target for pharmacotherapy. Imatinib Mesylate (Glivec) is a specific inhibitor of Bcr-Abl kinase. Imatinib shows high efficiency and low toxicity in treatment of CML patients. The main problem of imatinib treatment is the development of resistance. The mechanisms of resistance can be divided into two groups. The first group is characterized by reactivation of Bcr-Abl kinase in spite of continual imatinib presence. This can be caused by BCR-ABL amplification, overexpression or mutation in Abl kinase domain. Imatinib might not even reach the target Bcr-Abl protein (possible causes: drug efflux or imatinib binding to alpha1-acid glycoprotein). In the second group of resistance mechanisms, the Bcr-Abl kinase is inhibited but the resistance is maintained by other signal transducers (e.g. Src kinases). Standard cytogenetics as well as assay evaluating the phosphorylation status of Bcr-Abl substrate and/or sequencing of Abl kinase transcript can be used to test the mechanism of resistance. Treatment of patients can be re-evaluated on the basis of the status of IM resistance.

• MeSH
• bcr-abl fúzní proteiny MeSH
• benzamidy MeSH
• chemorezistence * MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• geny abl fyziologie   MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• piperaziny terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• signální transdukce MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• benzamidy MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH
• tyrosinkinasy MeSH

Chronic myeloid leukemia (CML) is a malignant hematopoietic disorder distinguished by the presence of a BCR‑ABL1 fused oncogene with constitutive kinase activity. Targeted CML therapy by specific tyrosine kinase inhibitors (TKIs) leads to a marked improvement in the survival of the patients and their quality of life. However, the development of resistance to TKIs remains a critical issue for a subset of patients. The most common cause of resistance are numerous point mutations in the BCR‑ABL1 gene, followed by less common mutations and multiple mutation-independent mechanisms. Recently, exosomes, which are extracellular vesicles excreted from normal and tumor cells, have been associated with drug resistance and cancer progression. The aim of the present study was to characterize the exosomes released by imatinib‑resistant K562 (K562IR) cells. The K562IR‑derived exosomes were internalized by imatinib‑sensitive K562 cells, which thereby increased their survival in the presence of 2 µM imatinib. The exosomal cargo was subsequently analyzed to identify resistance‑associated markers using a deep label‑free quantification proteomic analysis. There were >3,000 exosomal proteins identified of which, 35 were found to be differentially expressed. From this, a total of 3, namely the membrane proteins, interferon‑induced transmembrane protein 3, CD146 and CD36, were markedly upregulated in the exosomes derived from the K562IR cells, and exhibited surface localization. The upregulation of these proteins was verified in the K562IR exosomes, and also in the K562IR cells. Using flow cytometric analysis, it was possible to further demonstrate the potential of CD146 as a cell surface marker associated with imatinib resistance in K562 cells. Taken together, these results suggested that exosomes and their respective candidate surface proteins could be potential diagnostic markers of TKI drug resistance in CML therapy.

• Klíčová slova
• chronic myeloid leukemia, imatinib mesylate, drug resistance, proteomics, exosome, tyrosine kinase inhibitor, surface marker,
• MeSH
• antigen CD146 metabolismus   MeSH
• antigeny CD36 metabolismus   MeSH
• apoptóza účinky léků   MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   genetika   MeSH
• buňky K562 MeSH
• chemorezistence MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   patologie   MeSH
• exozómy účinky léků   metabolismus   MeSH
• imatinib mesylát farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• nádorové buněčné linie MeSH
• proteiny vázající RNA metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigen CD146 MeSH
• antigeny CD36 MeSH
• bcr-abl fúzní proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• IFITM3 protein, human MeSH Prohlížeč
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• membránové proteiny MeSH
• proteiny vázající RNA MeSH

Imatinib, a tyrosine kinase inhibitor, is currently the therapy of choice for gastrointestinal stromal tumor (GIST). The toxic effects of imatinib treatment are usually mild, and serious adverse events are rare. We report here the case of a patient with peritoneal metastases of GIST involving the pelvis treated by imatinib. Abdominal pain deteriorated early in the course of the therapy along with the enlargement of the tumors. The patient died suddenly, and the autopsy revealed pulmonary embolism originating from the deep vein thrombosis caused by the compression of common iliac vein by the tumor. The possibility of deep vein thrombosis caused by the compression of the veins by necrotic tumor should be considered in patients with abdominal or pelvic metastases of GIST, including patients treated with imatinib.

• MeSH
• benzamidy MeSH
• fatální výsledek MeSH
• gastrointestinální stromální tumory farmakoterapie   patologie   MeSH
• imatinib mesylát MeSH
• lidé středního věku MeSH
• lidé MeSH
• piperaziny škodlivé účinky   MeSH
• pitva MeSH
• protinádorové látky škodlivé účinky   MeSH
• pyrimidiny škodlivé účinky   MeSH
• tromboembolie chemicky indukované   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzamidy MeSH
• imatinib mesylát MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH