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1.
Prague Med Rep ; 120(2-3): 52-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31586504

RESUMO

Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.


Assuntos
Dasatinibe/farmacocinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Sistema Enzimático do Citocromo P-450 , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Ácido Gástrico , Humanos , Concentração de Íons de Hidrogênio , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
2.
Rinsho Ketsueki ; 60(9): 1140-1147, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597837

RESUMO

Imatinib, nilotinib, dasatinib, bosutinib, and ponatinib are tyrosine kinase inhibitors used to treat chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and target concentration intervention (TCI) are novel strategies that use concentration-controlled dosing (CCD) to attain a faster and more profound clinical response in patients with CML. The target plasma trough concentration (C0) of imatinib is 1,000 ng/ml to obtain a higher major molecular response (MMR) rate. Target nilotinib and bosutinib C0 of 900 and 62 ng/ml, respectively, are recommended to attain a better response, whereas a target ponatinib C0 of 21.3 ng/ml has been proposed to obtain a better response and decrease the risk of adverse events, such as vascular toxicity. Approaches for these four TKIs involve the use of TCI with specific target concentrations rather than TDM with a therapeutic range. Conversely, for dasatinib, a lower C0 of <4.33 ng/ml is the maximum toxic concentration recommended to avoid pleural effusion. Therefore, precision dosing using CCD of TKIs for CML could maximize the clinical benefit and minimize toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos de Anilina , Dasatinibe , Relação Dose-Resposta a Droga , Humanos , Mesilato de Imatinib , Imidazóis , Nitrilos , Proteínas Tirosina Quinases , Piridazinas , Pirimidinas , Quinolinas
4.
Cancer Sci ; 110(10): 3255-3266, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31402561

RESUMO

Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative-minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative-MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive-MRD with complete remission [CR] and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative-MRD or positive-MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new-generation TKI for high-risk patients are warranted to improve the outcomes after allogeneic HSCT.


Assuntos
Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Terapia Combinada , Dasatinibe/administração & dosagem , Dasatinibe/farmacologia , Feminino , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/farmacologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Indução de Remissão , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
6.
Anticancer Res ; 39(7): 3949-3954, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262926

RESUMO

We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.


Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Humanos , Masculino , Translocação Genética , Resultado do Tratamento
8.
Croat Med J ; 60(3): 250-254, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187953

RESUMO

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Dasatinibe/efeitos adversos , Dasatinibe/metabolismo , Síndrome Nefrótica/induzido quimicamente , Adulto , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Testes Farmacogenômicos , Fenótipo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/uso terapêutico
9.
Lancet Haematol ; 6(7): e375-e383, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31201085

RESUMO

BACKGROUND: All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission. METHODS: The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. FINDINGS: Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8-10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64-80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25-53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption. INTERPRETATION: Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR. FUNDING: Newcastle University and Bloodwise.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirimidinas/uso terapêutico , Recidiva , Resultado do Tratamento
12.
Zhonghua Xue Ye Xue Za Zhi ; 40(4): 281-287, 2019 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-31104438

RESUMO

Objectives: To explore the incidence and factors of severe leukopenia and/or thrombocytopenia in newly diagnosed patients with chronic myeloid leukemia (CML) to probe their impacts on cytogenetic and molecular responses, progression free survival (PFS) and overall survival (OS) . Methods: Data of newly diagnosed patients with CML in the chronic phase (CP) and/or accelerated phase (AP) were retrospectively collected and analyzed. Results: 855 CML patients [including 744 (87%) in the CP and 111 (13.0%) in the AP] were included in this study. 523 (61.2%) patients were male with a median age of 39 years (range, 14-87 years) . 749 (87.6%) patients received imatinib, 93 (10.9%) nilotinib, and 13 (1.5%) dasatinib, respectively as front-line therapy. At a median treatment of 1 month (range, 0.1-7.0 months) , 137 (16.0%) developed ≥grade 3 leukopenia and/or thrombocytopenia and recovered 0.6 month (range, 0.3-6.5 months) . Multivariate analysis showed that female gender (OR=1.5, 95%CI 1.0-2.2, P=0.033) , WBC ≥100×109/L (OR=1.9, 95%CI 1.3-2.8, P=0.001) , CP in Sokal high-risk (OR=2.2, 95%CI 1.2-3.9, P=0.005) , AP with ≥15% blast cells in blood or bone marrow (OR=5.1, 95%CI 1.9-13.3, P=0.001) were factors associated with higher incidence of ≥grade 3 leukopenia and/or thrombocytopenia. Severe leukopenia and/or thrombocytopenia with time of drug discontinuance >2 weeks was associated with lower probabilities of achieving complete cytogenetic (OR=0.4, 95%CI 0.3-0.6, P<0.001) , severe leukopenia and/or thrombocytopenia, no matter the time of drug discontinuance >2 weeks or ≤2 weeks, were associated with lower probabilities of achieving major molecular responses (OR=0.3, 95%CI 0.2-0.5, P<0.001; OR=0.7, 95%CI 0.5-1.0, P=0.036) and MR4.5 (OR=0.2, 95%CI 0.1-0.5, P=0.002; OR=0.7, 95%CI 0.4-1.1, P=0.110) ; however, those had no impacts on PFS and OS. Conclusions: Severe leukopenia and/or thrombocytopenia were common adverse events during TKI therapy. Female patients, WBC ≥100×109/L at diagnosed, CP in Sokal high-risk, CML-AP with ≥15% blast cells in blood or bone marrow were at high risk for higher incidence of severe leukopenia and/or thrombocytopenia. Those severe adverse events had impacts on lower cytogenetic and molecular response.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
J Exp Clin Cancer Res ; 38(1): 180, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036057

RESUMO

BACKGROUND: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. METHODS: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. RESULTS: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. CONCLUSION: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Oxirredutases Intramoleculares/genética , Neoplasias Pulmonares/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/genética , Receptores Virais/genética , Células A549 , Animais , Carcinogênese/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dasatinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
14.
Ann Hematol ; 98(8): 1885-1890, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31044260

RESUMO

There is little information about cardiovascular adverse event (CV-AE) incidence in chronic myeloid leukemia (CML) patients treated with bosutinib in the real-life practice. We identified 54 consecutive CML patients treated with bosutinib, stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 40-month cumulative incidence of CV-AEs was 25.2 ± 8.1%. Patients with the SCORE of high-very high showed a significantly higher incidence of CV-AEs (55 ± 12.9% vs 9 ± 9.5%; p = 0.002). Overall, 9 CV-AEs were reported, with 2 deaths attributed to CV-AE. In conclusion, the SCORE assessment before starting treatment is helpful in identifying CV-AE high-risk patients during bosutinib treatment.


Assuntos
Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Infarto do Miocárdio/induzido quimicamente , Nitrilos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/induzido quimicamente , Angina Pectoris/diagnóstico , Angina Pectoris/fisiopatologia , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Suscetibilidade a Doenças , Esquema de Medicação , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Nitrilos/administração & dosagem , Doenças Vasculares Periféricas/induzido quimicamente , Doenças Vasculares Periféricas/diagnóstico , Doenças Vasculares Periféricas/fisiopatologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Quinolinas/administração & dosagem , Estudos Retrospectivos
15.
Nat Commun ; 10(1): 2061, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053734

RESUMO

Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.


Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Dasatinibe/efeitos adversos , Podócitos/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Insuficiência Renal Crônica/patologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Animais , Linhagem Celular , Modelos Animais de Doenças , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Camundongos , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Estados Unidos , United States Food and Drug Administration
16.
Nat Neurosci ; 22(5): 719-728, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936558

RESUMO

Neuritic plaques, a pathological hallmark in Alzheimer's disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aß) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aß plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated ß-galactosidase activity. Molecular interrogation of the Aß plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aß triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aß load, and ameliorated cognitive deficits. Our findings suggest a role for Aß-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Senescência Celular , Dasatinibe/administração & dosagem , Células Precursoras de Oligodendrócitos/metabolismo , Quercetina/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/administração & dosagem , Animais , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Transgênicos , Placa Amiloide/ultraestrutura , Prosencéfalo/metabolismo , Prosencéfalo/ultraestrutura
18.
Drug Des Devel Ther ; 13: 825-843, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880916

RESUMO

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. At the molecular level, the disorder results from t(9;22)(q34;q11) reciprocal translocation between chromosomes, which leads to the formation of an oncogenic BCR-ABL gene fusion. Instead of progress in the understanding of the molecular etiology of CML and the development of novel therapeutic strategies, clinicians still face many challenges in the effective treatment of patients. In this review, we discuss the pathways of diagnosis and treatment of patients, as well as the problems appearing in the course of disease development. We also briefly refer to several aspects regarding the current knowledge on the molecular basis of CML and new potential therapeutic targets.


Assuntos
Antineoplásicos/farmacologia , Dasatinibe/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
19.
Nanomedicine (Lond) ; 14(7): 851-870, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30901283

RESUMO

AIM: To design, develop, optimize and evaluate sustained-release dasatinib-loaded gold nanoparticles (DSB-GNPs) to treat chronic myeloid leukemia (CML) by using quality by design. MATERIALS & METHODS: In this study, we performed risk assessment, optimization, in vitro characterizations, stability study, drug release studies, cytotoxicity study and in vivo pharmacokinetic evaluation. RESULTS: DSB-GNPs of desired size, entrapment, smooth, spherical, stable and sustained drug release for 48 h were achieved. DSB-GNPs exhibited significantly more percentage growth inhibition and enhanced systemic bioavailability compared with pure DSB. CONCLUSION: The in vitro and in vivo evaluation exhibited that the DSB-GNPs have a potential cytotoxic effect, systemic bioavailability and sustained release making them a promising system of DSB delivery in the treatment of chronic myeloid leukemia.


Assuntos
Dasatinibe/química , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Ouro/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nanopartículas Metálicas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Materiais Biocompatíveis/química , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Dasatinibe/farmacocinética , Preparações de Ação Retardada/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Humanos , Células K562 , Masculino , Tamanho da Partícula , Ratos Sprague-Dawley , Medição de Risco , Propriedades de Superfície
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