RESUMEN
The advent of BCR-ABL1 tyrosine kinase inhibitors has revolutionized the treatment and prognosis of chronic myeloid leukemia. Life expectancy for patients with chronic phase chronic myeloid leukemia now nears that of the healthy population; however, optimal outcomes require continuous tyrosine kinase inhibitor administration, which can impact patient quality of life. Consequently, the concept of treatment-free remission has been explored in patients achieving and sustaining a deep molecular response. Heterogeneous data exist with multiple tyrosine kinase inhibitors; however, nilotinib is currently the only therapy that has been approved by the US Food and Drug Administration for treatment-free remission. The decision to pursue treatment-free remission is one that relies heavily on both patient- and disease-related factors. Herein, we will discuss relevant considerations to be made when determining an optimal candidate for treatment-free remission.
Asunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mieloide de Fase Crónica/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Calidad de Vida , Inducción de Remisión/métodos , Resultado del TratamientoRESUMEN
To explore the differences in glucose-lipid metabolism profiles among the 3 TKIs, we designed a retrospective study to compare the onset of hyperglycaemia, hypertriglyceridemia, hypercholesterolemia and hyper-low density lipoprotein (LDL)-cholesterolemia in the patients with normal baseline glucose-lipid profiles and had no medical record of cardio- or cerebro-vascular diseases and/or metabolic syndrome diseases, and identify variables associated with them. 370 chronic myeloid leukaemia patients receiving dasatinib, nilotinib or imatinib therapy ≥3 months were retrospectively reviewed. During TKI-therapy, the mean fasting glucose, triglyceride, cholesterol, and LDL-cholesterol levels increased significantly in both dasatinib and nilotinib cohorts compared with the imatinib cohort. In multivariate analyses, dasatinib was the factor significantly associated with both poor hyperglycaemia- and hypertriglyceridemia-free survival. In addition, nilotinib was significantly associated with more occurrences of hyperglycaemia and hypercholesterolemia; increasing age was significantly associated with more occurrences of hyperglycaemia and hypertriglyceridemia. We concluded that dasatinib, similar to nilotinib, has the adverse impact on glucose-lipid metabolism compared with imatinib.
Asunto(s)
Antineoplásicos/efectos adversos , Dasatinib/efectos adversos , Glucosa/metabolismo , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , LDL-Colesterol/sangre , Dasatinib/farmacología , Dasatinib/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Hiperglucemia/sangre , Hiperglucemia/inducido químicamente , Hipertrigliceridemia/sangre , Hipertrigliceridemia/inducido químicamente , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Terapia Recuperativa , Adulto JovenRESUMEN
Secreted frizzled-related protein 2 (SFRP2) has been reported to act as a tumor suppressors. This study aims to detect the biological role of SFRP2 in advanced chronic myeloid leukemia (CML). In this study we examined bone marrow samples from 45 CML patients and 10 healthy donors. K562 and KCL22â¯cells were cultured and treated with demethylation drug and histone deacetylase inhibitor (HDACi). KCL22 and K562â¯cells were transfected with lentiviral vector (LV)-SFRP2, LV-control. The cells were then subjected to proliferation and apoptosis assays, real time polymerase chain reaction (PCR), Methylation-specific PCR (MSP), Western blotting, co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP), We found that SFRP2 was down-regulated in the accelerated and blast phase of CML, whereas, the levels of WNT1, WNT3 and WNT5A were up-regulated in the accelerated and blast phase of CML. Overexpression SFRP2 inhibited proliferation, promoted apoptosis and activated the WNT pathway. CoIP-MS results showed that SFRP2 interacted with WNT1 and WNT5A. ChIP-seq result indicated that the promoter of H3K4me3 and H3K27me3 were able to interact with SFRP2. In conclusion, our findings demonstrated the SFRP2 act as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs and HDACi as a potential CML treatment strategy.
Asunto(s)
Epigénesis Genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas de la Membrana/genética , Adolescente , Adulto , Anciano , Apoptosis/genética , Crisis Blástica/genética , Crisis Blástica/metabolismo , Crisis Blástica/patología , Proliferación Celular/genética , Niño , Metilación de ADN/genética , Regulación hacia Abajo , Femenino , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Acelerada/genética , Leucemia Mieloide de Fase Acelerada/metabolismo , Leucemia Mieloide de Fase Acelerada/patología , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Vía de Señalización Wnt/genética , Adulto JovenRESUMEN
Patients diagnosed with chronic myeloid leukemia (CML) and treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs) have long life spans. Selection of an appropriate first-line therapy can be difficult as both the unique characteristics of each TKI and patient need to be taken into account to find the optimal match. Patient characteristics include comorbidities, concomitant medications, lifestyle, risk factors, BCR-ABL1 transcript type (e.g. b2a2 or b3a2) and additional chromosomal abnormalities. Just as patients differ, side effects, drug-drug interactions, administration plans, dosing schedules and treatment-related expenses across TKIs also vary. Alignment of these characteristics with the appropriate TKI is key to successfully initiating CML treatment. Continued success relies on communication between the patient and the healthcare team, adherence and optimization of therapy once it is initiated. In this review, we discuss these factors, in addition to TKI efficacy and safety, the cost of therapy, the future of treating CML and treatment-free remission.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos como Asunto , Costos de los Medicamentos , Humanos , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Cumplimiento de la Medicación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: This study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter. METHODS: This substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter). RESULTS: The rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months. CONCLUSIONS: The association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib.
Asunto(s)
Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Pirimidinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Femenino , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Masculino , Persona de Mediana Edad , Transcripción GenéticaRESUMEN
Acquired resistance to imatinib is frequently associated with poor clinical outcome of chronic myeloid leukemia (CML) patient. To date, evidence indicates that protein glycosylation and its upstream regulators might be implicated in tumorigenesis and chemoresistance occurrence. In current study we initially explored N-glycan profiles on the surface of CML cell lines and bone marrow mononuclear cells (BMMC) of CML patients by using mass spectrometry (MS) analysis. An elevated sialylation was detected in K562R cells (CML cells with imatinib resistance phenotype) compare to K562 cells. By quantitative real time-PCR (qRT-PCR) and western blotting analysis we observed that imatinib resistant K562R cells exhibited marked high levels of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase (ST3Gal IV) as compared to imatinib sensitive K562 cells. Further studies revealed that manipulated expression of ST3GAL IV led to the significant alterations of cell cycle distribution, apoptotic signal, cell proliferation and the effectiveness of imatinib treatment. Using microRNA array, miRNA database searching and luciferase reporter assay, we identified that miR-224 and let-7i directly regulate the expression of ST3GAL IV gene. Moreover, engineered expression of miR-224 and let-7i in K562 and K562R cells could significantly affect ST6Gal IV-induced proliferation rate and drug-resistance. Thus we propose that miR-224 and let-7i regulate the proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV.
Asunto(s)
Apoptosis , Resistencia a Antineoplásicos , Leucemia Mieloide de Fase Crónica/metabolismo , MicroARNs/genética , Sialiltransferasas/genética , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Regulación hacia Abajo , Femenino , Humanos , Mesilato de Imatinib/farmacología , Leucemia Mieloide de Fase Crónica/genética , Masculino , Persona de Mediana Edad , Sialiltransferasas/metabolismo , beta-Galactosida alfa-2,3-SialiltransferasaRESUMEN
B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells. We proved that during combined treatment, inhibition of constitutive signal transducer and activator of transcription (STAT) 5 activation by IM allowed the specific enhancement of the STAT1 dependent, direct upregulation of BCL6 by IFNγ in CML cells. By using colony-forming assay, we found that IFNγ enhanced the ex vivo colony or cluster-forming capacity of human CML stem cells in the absence or presence of IM, respectively. Furthermore, inhibition of the transcriptional repressor function of BCL6 in the presence of IM and IFNγ almost completely blocked the cluster formation of human CML stem cells. On the other hand, by using small interfering RNA knockdown of BCL6, we demonstrated that in an IM-treated CML line the antiapoptotic effect of IFNγ was independent of BCL6 upregulation. We found that IFNγ also upregulated several antiapoptotic members of the BCL2 and BIRC gene families in CML cells, including the long isoform of MCL1, which proved to be essential for the antiapoptotic effect of IFNγ in an IM-treated CML line. Our results suggest that combination of TKIs with BCL6 and MCL1 inhibitors may potentially lead to the complete eradication of CML stem cells.
Asunto(s)
Mesilato de Imatinib/uso terapéutico , Interferón gamma/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Factor de Transcripción STAT1/metabolismo , Antígenos CD34/metabolismo , Línea Celular Tumoral , Humanos , Mesilato de Imatinib/farmacología , Interferón gamma/farmacología , Leucaféresis , Leucemia Mieloide de Fase Crónica/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Neuronal/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Neuronal/metabolismo , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Proteína Letal Asociada a bcl/efectos de los fármacos , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Imatinib is actively transported by organic cation transporter-1 (OCT-1) influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Herein we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1+ cell lines, peroxisome proliferator-activated receptor γ agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor γ antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to BCR-ABL kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor γ-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor γ transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; P<0.0001), suggesting that peroxisome proliferator-activated receptor γ activation has a negative impact on the intracellular uptake of imatinib and consequent BCR-ABL kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor γ activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor γ agonist pioglitazone was reported to act synergistically with imatinib, targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor γ ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor γ activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor γ transcriptional activity.
Asunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , PPAR gamma/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Células Cultivadas , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Regulación Leucémica de la Expresión Génica , Células HL-60 , Humanos , Mesilato de Imatinib/farmacocinética , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Leucemia Mieloide de Fase Crónica/patología , Leucocitos Mononucleares/metabolismo , Transportador 1 de Catión Orgánico/genética , Transportador 1 de Catión Orgánico/metabolismo , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidoresRESUMEN
BACKGROUND: Chronic Myeloid Leukemia was always referred as a unique cancer due to the apparent independence from tumor suppressors' deletions/mutations in the early stages of the disease. However, it is now well documented that even genetically wild-type tumor suppressors can be involved in tumorigenesis, when functionally inactivated. In particular, tumor suppressors' functions can be impaired by subtle variations of protein levels, changes in cellular compartmentalization and post-transcriptional/post-translational modifications, such as phosphorylation, acetylation, ubiquitination and sumoylation. Notably, tumor suppressors inactivation offers challenging therapeutic opportunities. The reactivation of an inactive and genetically wild-type tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. MAIN BODY: Chronic Myeloid Leukemia (CML) could be considered as the paradigm for non-genomic loss of function of tumor suppressors due to the ability of BCR-ABL to directly promote functionally inactivation of several tumor suppressors. SHORT CONCLUSION: In this review we will describe new insights on the role of FoxO, PP2A, p27, BLK, PTEN and other tumor suppressors in CML pathogenesis. Finally, we will describe strategies to promote tumor suppressors reactivation in CML.
Asunto(s)
Leucemia Mieloide de Fase Crónica/genética , Proteínas Supresoras de Tumor/genética , Animales , Expresión Génica , Regulación Leucémica de la Expresión Génica , Genoma Humano , Humanos , Leucemia Mieloide de Fase Crónica/metabolismo , Mutación , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients' long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Sustitución de Medicamentos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Leucemia Mieloide de Fase Crónica/mortalidad , Terapia Molecular Dirigida , Guías de Práctica Clínica como Asunto , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Retratamiento , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
A better understanding of events triggering chronic myeloid leukemia progression is critical for optimized clinical management of chronic myeloid leukemia (CML). We sought to validate that increased expression of Musashi 2 (MSI2), a post-transcription regulator, is associated with progression and prognosis. Screening of 152 patients with CML showed that MSI2 was significantly decreased among patients with CML in chronic phase (CP) at diagnosis (p < 0.0001), but found no significant difference between the normal control group and treated patients with CML in CP. Moreover MSI2 was significantly increased (p < 0.0001) in patients with advance disease (AD) CML. Furthermore, our human hematopoietic cell line data imply that MSI2 and BCR-ABL1 mRNA expression are correlated. However, these data cast a doubt on earlier reports that MSI2 effects HES1 expression via NUMB-NOTCH signaling.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide de Fase Crónica/metabolismo , Leucemia Mieloide de Fase Crónica/patología , Proteínas de Unión al ARN/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Células Madre Hematopoyéticas/patología , Humanos , Técnicas para Inmunoenzimas , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Tasa de Supervivencia , Regulación hacia Arriba , Adulto JovenRESUMEN
Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients' CD34(+) cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34(+) CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients.
Asunto(s)
Basófilos/patología , Diferenciación Celular/efectos de los fármacos , Eosinófilos/patología , Factor de Transcripción Ikaros/antagonistas & inhibidores , Leucemia Mieloide de Fase Crónica/patología , Factor de Transcripción STAT5/metabolismo , Animales , Antígenos CD34/metabolismo , Apoptosis/efectos de los fármacos , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Progresión de la Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Citometría de Flujo , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Técnicas para Inmunoenzimas , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT5/genéticaRESUMEN
PURPOSE: We evaluated the population pharmacokinetics (PPK) and exposure-response relationship of imatinib mesylate in Iranian patients with chronic myeloid leukemia (CML).This study was designed to assess steady state (SS) imatinib trough concentrations (Cmin) and pharmacokinetics parameters of imatinib in patients with CML in chronic phase after at least 12-month treatment. METHODS: Plasma concentrations from a randomized controlled trial consist of 61 patients who received oral imatinib at doses ranged between 300 and 800 mg in various dosing interval, which were quantified using a validated reversed-phase high-performance liquid chromatographic method with UV detection method on different occasions at SS and evaluated using PPK model. RESULTS: A one-compartment model with zero-order absorption and a lag time was sufficient in describing the concentration-time profile. Inter-individual variability (IIV) was modeled for all parameters. Oral clearance (CL/F) and the volume of distribution (V/F) were estimated to 10.8 L/h with 30 % IIV and 265 L with 53 % IIV, respectively. Inter-occasion variability (IOV) was included in CL/F (17 %) and V/F (22 %).The proportional residual error of the model was 8 %. CONCLUSIONS: Simulation analysis from individual parameters shows exposure to imatinib is highly variable among patients. Imatinib trough plasma levels <1,257 ng/mL were associated with lower rates of major molecular response. Because of the wide IIV compared with IOV with imatinib in our study, trough levels may play a role in investigating instances of suboptimal response.
Asunto(s)
Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Modelos Biológicos , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Teorema de Bayes , Benzamidas/administración & dosificación , Benzamidas/sangre , Benzamidas/uso terapéutico , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Irán , Leucemia Mieloide de Fase Crónica/sangre , Leucemia Mieloide de Fase Crónica/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/sangre , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Pirimidinas/uso terapéutico , Curva ROC , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
This study was aimed at investigating the reversal effect of oroxylin A, a naturally bioactive monoflavonoid separated and purified from Scutellaria baicalensis Georgi, in human chronic myeloid leukemia (CML) and the underlying mechanisms. The results showed that CXCL12 could enhance the resistance of K562 cells to adriamycin (ADM) by increasing the expression of CXCR4, up-regulating the downstream PI3K/Akt pathway, and promoting translocation of NF-κB dimers into nucleus and subsequently decreasing the expression of apoptosis-related proteins in K562 cells. And we found that ADM resistance was partially reversed by CXCR4 siRNA transfection. Moreover, the sensitivity enhancement of oroxylin A was demonstrated by decreasing the expression of CXCR4 at both protein and mRNA levels, via PI3K/Akt/NF-κB pathway and triggering the apoptosis pathway in vitro. In addition, the in vivo study showed that oroxylin A increased apoptosis of leukemic cells with low systemic toxicity, and the mechanism was the same as in vitro study. In conclusion, all these results showed that oroxylin A improved the sensitivity of K562/ADM cells by increasing apoptosis in leukemic cells and decreasing the expression of CXCR4 and PI3K/Akt/NF-κB pathway, and probably served as a most promising agent for CML treatment.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Quimiocina CXCL12/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Flavonoides/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Femenino , Flavonoides/efectos adversos , Flavonoides/farmacología , Humanos , Leucemia Mieloide de Fase Crónica/metabolismo , Ratones , Ratones Desnudos , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasa/química , Fosfatidilinositol 3-Quinasa/metabolismo , Interferencia de ARN , Distribución Aleatoria , Receptores CXCR4/agonistas , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance.
Asunto(s)
Antígenos CD34/biosíntesis , Proteínas de Fusión bcr-abl/metabolismo , Interleucinas/metabolismo , Leucemia Mieloide de Fase Crónica/metabolismo , Células Madre Neoplásicas/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Antígenos CD34/inmunología , Benzamidas/farmacología , Citocinas/biosíntesis , Interacciones Farmacológicas , Femenino , Proteínas de Fusión bcr-abl/inmunología , Humanos , Mesilato de Imatinib , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/inmunología , Interleucinas/farmacología , Janus Quinasa 2/metabolismo , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/inmunología , Leucemia Mieloide de Fase Crónica/patología , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Piperazinas/farmacología , Pirimidinas/farmacología , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/inmunología , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia ArribaRESUMEN
Despite undisputed success of tyrosine kinase inhibitors in the therapy of chronic myeloid leukemia (CML), development of drug resistance and inability to cure the disease challenge clinicians and researchers. Additionally, recent reports regarding cardiovascular toxicities of second and third generation tyrosine kinase inhibitors prove that there is still a place for novel therapeutic combinations in CML. We have previously shown that statins are able to modulate activity of chemotherapeutics or antibodies used in oncology. Therefore, we decided to verify that statins are able to potentiate antileukemic activity of imatinib, still a frontline treatment of CML. Lovastatin, a cholesterol lowering drug, synergistically potentiates antileukemic activity of imatinib in cell lines and in primary CD34+ CML cells from patients in different phases of the disease, including patients resistant to imatinib with no detectable mutations. This effect is related to increased intracellular concentration of imatinib in CD34+ CML cells and cell lines measured using uptake of (14)C-labeled imatinib. Lovastatin does not influence influx but significantly inhibits efflux of imatinib mediated by ATP-binding cassette (ABC) transporters: ABCB1 and ABCG2. The addition of cholesterol completely reverses these effects. Statins do not affect expression of ABCB1 and ABCG2 genes. The effects are drug-class specific, as observed with other statins. Our results suggest that statins may offer a valuable addition to imatinib in a select group of CML patients.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/farmacología , Benzamidas/farmacología , Leucemia Mieloide de Fase Crónica/fisiopatología , Proteínas de Neoplasias/antagonistas & inhibidores , Piperazinas/farmacología , Pirimidinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Animales , Antineoplásicos/uso terapéutico , Western Blotting , Línea Celular , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Mesilato de Imatinib , Células K562 , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/metabolismo , Lovastatina/farmacología , RatonesRESUMEN
Dasatinib is a highly potent BCR-ABL kinase inhibitor with established efficacy and safety in imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. In the global phase III DASISION trial in patients with newly diagnosed chronic phase CML (CML-CP), dasatinib was found to have an acceptable safety profile and demonstrated significantly faster and higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. Here, we report the results of a subset analysis of Japanese patients enrolled in the DASISION trial, showing safety and efficacy profiles generally consistent with patients enrolled worldwide, including higher response rates (CCyR, MMR) with dasatinib compared with imatinib and similar high rates of progression-free and overall survival with both therapies. However, the small sample size of the present study limits the strength of these conclusions, and further exploration is needed to confirm any differences observed in Japanese patients compared with the total treated population. These findings support the use of dasatinib 100 mg QD as a first-line treatment in Japanese patients with newly diagnosed CML-CP.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Dasatinib , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Japón , Leucemia Mieloide de Fase Crónica/sangre , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Análisis de Supervivencia , Tiazoles/efectos adversos , Adulto JovenRESUMEN
Leukemic stem cells in chronic phase chronic myelogenous leukemia (CP-CML) are responsible for disease persistence and eventual drug resistance, most likely because they survive, expand, and are sustained through interactions with their microenvironment. Bone morphogenetic proteins 2 (BMP2) and 4 (BMP4) regulate the fate and proliferation of normal hematopoietic stem cells, as well as interactions with their niche. We show here that the intrinsic expression of members of the BMP response pathway are deregulated in CML cells with differences exhibited in mature (CD34(-)) and immature (CD34(+)) compartments. These changes are accompanied by altered functional responses of primitive leukemic cells to BMP2 and BMP4 and strong increases in soluble BMP2 and BMP4 in the CML bone marrow. Using primary cells and a cell line mimicking CP-CML, we found that myeloid progenitor expansion is driven by the exposure of immature cells overexpressing BMP receptor Ib to BMP2 and BMP4. In summary, we demonstrate that deregulation of intracellular BMP signaling in primary CP-CML samples corrupts and amplifies their response to exogenous BMP2 and BMP4, which are abnormally abundant within the tumor microenvironment. These results provide new insights with regard to leukemic stem cell biology and suggest possibilities for the development of novel therapeutic tools specifically targeting the CML niche.
Asunto(s)
Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 4/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Leucemia Mieloide de Fase Crónica/metabolismo , Leucemia Mieloide de Fase Crónica/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Línea Celular Tumoral , Humanos , Leucemia Mieloide de Fase Crónica/genética , Modelos Biológicos , Transducción de Señal , Nicho de Células Madre , Microambiente Tumoral , Regulación hacia ArribaRESUMEN
BACKGROUND: The characteristic expression of the constitutively active oncoprotein, BCR-ABL tyrosine kinase, in chronic myeloid leukemia (CML) was the basis for the development of BCR-ABL tyrosine kinase inhibitors for treatment. Three BCR-ABL inhibitors, imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). METHODS: This article reviews the key phase III clinical trials supporting the use of first-line imatinib, nilotinib, and dasatinib in patients with CML-CP, as well as findings of supportive phase II studies. RESULTS: At the time of its approval in 2001, imatinib induced unprecedented response rates in patients with CML-CP; however, resistance and intolerance to imatinib prevent 20% to 30% of patients from deriving full therapeutic benefit. Nilotinib and dasatinib, both approved in 2010 for first-line CML-CP treatment, are more potent than imatinib and less susceptible to imatinib resistance mechanisms. Comparative clinical trials of each agent with imatinib have shown that they are associated with significantly deeper and more rapid responses than standard-dose imatinib, without compromising safety. CONCLUSIONS: Given that evidence suggests achievement of an early response is predictive of improved long-term outcomes, earlier use of these compounds may lead to more rapid, deeper responses corresponding with improvements in patient outcome. Although future studies will benefit from more uniform definitions of end points and methods of analysis, data from published studies of first-line BCR-ABL inhibitor treatment for patients with newly diagnosed CML-CP support the use of dasatinib or nilotinib in place of imatinib.
Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Dasatinib , Humanos , Leucemia Mieloide de Fase Crónica/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Proyectos de Investigación , Tiazoles/efectos adversos , Tiazoles/uso terapéutico , Resultado del TratamientoRESUMEN
The role of p27(kip1) in Chronic Myeloid Leukemia (CML) has been well studied in relation to its function as a cell cycle inhibitor. However, its cytoplasmic function especially in CML remains to be seen. We studied the localization of p27(kip1) and its function during the progression of CML from chronic to blast phase. Our investigations revealed an increased localization of p27(kip1) in the cytoplasm of CD34(+) cells in the blast phase compared to chronic phase. Cytoplasmic p27(kip1) was found to modulate RhoA activity in CD34(+) stem and progenitor cells. Further, RhoA activity was shown to be dependent on cytoplasmic p27(kip1) which in turn was dependent on p210(Bcr-Abl) kinase activity. Interestingly, RhoA activity was observed to affect cell survival in the presence of imatinib through the SAPK/JNK pathway. Accordingly, inhibition of SAPK/JNK pathway using SP600125 increased apoptosis of K562 cells in presence of imatinib. Our results, for the first time, thus reveal a crucial link between cytoplasmic p27(kip1), RhoA activity and SAPK/JNK signalling. To this effect we observed a correlation between increased cytoplasmic p27(kip1), increased RhoA protein levels, decreased RhoA-GTP levels and increased SAPK/JNK phosphorylation in blast phase CD34(+) cells compared to chronic phase CD34(+) cells.