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1.
Leuk Lymphoma ; 62(4): 819-827, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33167741

RESUMEN

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n = 100) and angioimmunoblastic T-cell lymphoma (AITL, n = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.


Asunto(s)
Linfoma de Células T Periférico , Linfoma de Células T , Hospitales , Humanos , Japón/epidemiología , Linfoma de Células T/diagnóstico , Linfoma de Células T/epidemiología , Linfoma de Células T/terapia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/epidemiología , Linfoma de Células T Periférico/terapia , Pronóstico , Estudios Retrospectivos
2.
Int J Hematol ; 111(3): 388-395, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31897888

RESUMEN

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18-80 years with platelet counts of < 20 × 109/l, or < 50 × 109/l and bleeding symptoms. The primary endpoints are the proportion of complete response (CR) plus partial response (R) on day 180 after the completion of the 46-day HDD. Twenty-three patients were enrolled. Test for Helicobacter pylori (H. pylori) was positive for 6 patients and negative for 17 patients. In positive patients, 5 were received successful H. pylori eradication therapy. The proportion of CR + R was 60.9% (14/23) with 90% confidence interval of 41.7-77.8%. For patients with positive H. pylori and successful eradication, the proportion of CR + R was 80.0% (4/5). There was one grade 4 adverse event. Although we have enrolled relatively old, severe ITP patients with a median age of 63 years in this study, the efficacy was comparable to the reported clinical trials with HDD therapy.


Asunto(s)
Dexametasona/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adulto , Humanos , Masculino , Quimioterapia por Pulso , Resultado del Tratamiento
3.
EJHaem ; 1(2): 507-516, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35844987

RESUMEN

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose-adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP-R) in this population. ASCT-ineligible elderly patients with relapsed or refractory DLBCL received dose-adjusted GDP-R in each 28-day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Thirty-three patients were enrolled and received dose-adjusted GDP-R. The median age was 75 years (range: 68-87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1-93.0%), with a CR rate of 58.6% (90% CI, 41.7-74.1%). At a median follow-up of 20.9 months, the 2-year PFS rate was 46.8% (90% CI, 30.7-61.5%) and the 2-year overall survival rate was 63.2% (90% CI, 45.8-76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose-adjusted GDP-R is a promising salvage regimen for ASCT-ineligible elderly patients with relapsed DLBCL after rituximab-containing chemotherapy and warrants further investigation.

4.
Acta Med Okayama ; 72(2): 197-201, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29674771

RESUMEN

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /µL, or with <50, 000/ µL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP.


Asunto(s)
Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adulto , Anciano , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Dexametasona/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Glucocorticoides/administración & dosificación , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/aislamiento & purificación , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Humanos , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/uso terapéutico , Adulto Joven
6.
Int J Hematol ; 105(5): 587-597, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28044259

RESUMEN

The poor prognosis of adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is attributed to leukemia cells that are protected by the bone marrow (BM) microenvironment. In the present study, we explored the pharmacological targeting of mesenchymal stromal/stem cells in BM (BM-MSCs) to eliminate chemoresistant BCP-ALL cells. Human BCP-ALL cells (NALM-6 cells) that adhered to human BM-MSCs (NALM-6/Ad) were highly resistant to multiple anti-cancer drugs, and exhibited pro-survival characteristics, such as an enhanced Akt/Bcl-2 pathway and increased populations in the G0 and G2/S/M cell cycle stages. Bortezomib, a proteasome inhibitor, interfered with adhesion between BM-MSCs and NALM-6 cells and up-regulated the matricellular protein SPARC (secreted protein acidic and rich in cysteine) in BM-MSCs, thereby reducing the NALM-6/Ad population. Inhibition of SPARC expression in BM-MSCs using a small interfering RNA enhanced adhesion of NALM-6 cells. Conversely, recombinant SPARC protein interfered with adhesion of NALM-6 cells. These results suggest that SPARC disrupts adhesion between BM-MSCs and NALM-6 cells. Co-treatment with bortezomib and doxorubicin prolonged the survival of BCP-ALL xenograft mice, with a significant reduction of leukemia cells in BM. Our findings demonstrate that bortezomib contributes to the elimination of BCP-ALL cells through disruption of their adhesion to BM-MSCs, and offer a novel therapeutic strategy for BCP-ALL through targeting of BM-MSCs.


Asunto(s)
Antineoplásicos/farmacología , Linfocitos B/patología , Células de la Médula Ósea , Bortezomib/farmacología , Células Madre Mesenquimatosas , Terapia Molecular Dirigida , Osteonectina/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Animales , Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones SCID , Trasplante de Neoplasias , Osteonectina/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos
7.
Stem Cells ; 32(8): 2245-55, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24648356

RESUMEN

Parathyroid hormone (PTH) stimulates hematopoiesis in mouse models. The involvement of osteoblasts in this process has been well investigated; however, the effects of PTH on human hematopoiesis and bone marrow mesenchymal stromal cells (BM-MSCs) are unclear. Here, we show that BM-MSCs contribute to the hematopoiesis-stimulating effects of PTH via upregulation of cadherin-11 (CDH11). When culture-expanded human BM-MSCs were stimulated with PTH, their ability to expand cocultured CD34(+) hematopoietic progenitor cells (HPCs) was enhanced. Furthermore, when PTH-treated BM-MSCs were subcutaneously implanted into NOD/SCID mice, the induction of hematopoietic cells was enhanced. Culture-expanded human BM-MSCs expressed CDH11, and the level of CDH11 expression increased following PTH stimulation. Depletion of CDH11 expression in BM-MSCs using small interfering RNA abolished the enhancement of HPC expansion by PTH-treated BM-MSCs. In lethally irradiated mice that underwent BM transplantation, CDH11 expression in BM-MSCs was higher and survival was better in PTH-treated mice than in control mice. The number of hematopoietic cells in BM and the number of red blood cells in peripheral blood were higher in PTH-treated mice than in control mice. Our results demonstrate that PTH stimulates hematopoiesis through promoting the upregulation of CDH11 expression in BM-MSCs, at least in part. PTH treatment may be an effective strategy to enhance the ability of BM-MSCs to support hematopoiesis.


Asunto(s)
Células de la Médula Ósea/metabolismo , Cadherinas/metabolismo , Hematopoyesis/fisiología , Células Madre Mesenquimatosas/metabolismo , Hormona Paratiroidea/metabolismo , Animales , Células de la Médula Ósea/citología , Diferenciación Celular/fisiología , Células Cultivadas , Técnicas de Cocultivo , Femenino , Técnicas de Silenciamiento del Gen , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Xenoinjertos , Humanos , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos NOD , Ratones SCID , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia Arriba
8.
Stem Cells ; 32(3): 730-40, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24115241

RESUMEN

The transcription factor CCAAT/enhancer-binding protein ß (C/EBPß) regulates the differentiation of a variety of cell types. Here, the role of C/EBPß expressed by bone marrow mesenchymal stromal cells (BMMSCs) in B-cell lymphopoiesis was examined. The size of the precursor B-cell population in bone marrow was reduced in C/EBPß-knockout (KO) mice. When bone marrow cells from C/EBPß-KO mice were transplanted into lethally irradiated wild-type (WT) mice, which provide a normal bone marrow microenvironment, the size of the precursor B-cell population was restored to a level equivalent to that generated by WT bone marrow cells. In coculture experiments, BMMSCs from C/EBPß-KO mice did not support the differentiation of WT c-Kit(+) Sca-1(+) Lineage(-) hematopoietic stem cells (KSL cells) into precursor B cells, whereas BMMSCs from WT mice did. The impaired differentiation of KSL cells correlated with the reduced production of CXCL12/stromal cell-derived factor-1 by the cocultured C/EBPß-deficient BMMSCs. The ability of C/EBPß-deficient BMMSCs to undergo osteogenic and adipogenic differentiation was also defective. The survival of leukemic precursor B cells was poorer when they were cocultured with C/EBPß-deficient BMMSCs than when they were cocultured with WT BMMSCs. These results indicate that C/EBPß expressed by BMMSCs plays a crucial role in early B-cell lymphopoiesis.


Asunto(s)
Linfocitos B/metabolismo , Células de la Médula Ósea/citología , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Linfopoyesis , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Animales , Linfocitos B/patología , Proteína beta Potenciadora de Unión a CCAAT/deficiencia , Diferenciación Celular , Supervivencia Celular , Células Cultivadas , Microambiente Celular , Quimiocina CXCL12/biosíntesis , Técnicas de Cocultivo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Leucemia de Células B/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteogénesis , Células Precursoras de Linfocitos B/citología
9.
J Clin Med Res ; 5(1): 57-60, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23390477

RESUMEN

BACKGROUND: Iron chelation therapy is useful against the over-accumulation of iron and is expected to reduce oxidative stress resulting from the Fenton reaction and Haber-Weiss reaction. We monitored oxidative status and serum ferritin levels after in vivo administration of deferasirox (DFS) and studied the in vitro effects of iron chelators on neutrophil function. METHODS: Nine patients suffering from transfusion dependency were recruited for this study, and derivatives of reactive oxygen metabolite (dROM) tests to detect serum hydroperoxide levels were evaluated in addition to serum ferritin levels. Human neutrophil reactive oxygen species (ROS) production was determined with flow cytometry. RESULTS: Ferritin levels decreased after DFS treatment (P = 0.068), and a significant reduction in dROM levels was measured (P = 0.031). Fifty microM DFS significantly inhibited ROS production induced by fMLP in vitro (P < 0.0001), and tended to inhibit that induced by PMA. On the other hand, deferioxamine failed to inhibit ROS production even at high concentrations. CONCLUSIONS: In vivo administration of DFS resulted in the reduction of oxidative stress, and this effect was considered to depend not only on a reduction in iron storage but also on the ability of DFS to inhibit neutrophil ROS production in vitro at clinically relevant plasma levels. Further studies are needed to examine the effects of iron chelators.

10.
Int J Hematol ; 89(5): 709-13, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19430860

RESUMEN

Thymic mucosa-associated lymphoid tissue (MALT) lymphoma shows distinct immunological characteristics, such as the expression of the IgA isotype, the frequent presence of immunoglobulin abnormalities, and a strong association with autoimmune disease, especially Sjögren's syndrome (SjS). We report a case of thymic MALT lymphoma, who exhibited biphasic changes in her clinical characteristics during the 4-year observation period after thymectomy. A 71-year-old woman was admitted because of suspected SjS. A diagnosis of primary thymic MALT lymphoma was made, and SjS was confirmed. Serological abnormalities such as polyclonal hypergammaglobulinemia, IgA M protein, and elevated levels of rheumatoid factor were noted. These abnormalities improved rapidly after the thymectomy, but did not completely disappear. Interestingly, the remaining abnormalities, which can be ascribed to the proliferation of B cells throughout the body under the influence of SjS, have been improving slowly but steadily during the 4-year observation period. It is suspected that the removal of the tumor by thymectomy has more or less normalized the immunological environment and alleviated the SjS disease activity.


Asunto(s)
Linfoma de Células B de la Zona Marginal/complicaciones , Síndrome de Sjögren/diagnóstico , Neoplasias de la Tiroides/complicaciones , Anciano , Linfocitos B/patología , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/cirugía , Timectomía , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugía , Resultado del Tratamiento
11.
Int J Hematol ; 84(1): 74-8, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16867907

RESUMEN

Although CD20- relapses of B-cell lymphoma following rituximab therapy have increasingly been reported recently, coexistence of both the original and selected clones on relapse in a single patient have not been described. We experienced such a case with rare CD5+ intravascular lymphomatosis (IVL). A 46-year-old woman was admitted because of IVL complicated with cauda equina syndrome and pulmonary infarction. Complete remission was successfully achieved with multidrug chemotherapy in combination with rituximab. However, the disease recurred after 8 months with leukemic progression and meningeal involvement. The phenotype of the abnormal lymphocytes in the peripheral blood was fundamentally the same (CD20+CD5+CD10-CD19+CD23-sIglambda+) as that of the cells in the cerebrospinal fluid (CSF). However, CD20 expression was decreased remarkably compared with that in the CSF and that in the bone marrow before therapy. The targeting of CD20 molecules on the tumor cell surface by rituximab may have provided a selective pressure on lymphoma cells. The escape phenomenon of the lymphoma cells from rituximab was observed by simultaneously comparing the CD20 expression of cells in the peripheral blood and in a site of sanctuary from rituximab, the CSF.


Asunto(s)
Antígenos CD20 , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígenos CD5 , Linfoma de Células B/prevención & control , Neoplasias Meníngeas/prevención & control , Escape del Tumor/efectos de los fármacos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Antígenos CD20/líquido cefalorraquídeo , Antígenos CD5/líquido cefalorraquídeo , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Linfocitos/metabolismo , Linfocitos/patología , Linfoma de Células B/líquido cefalorraquídeo , Linfoma de Células B/patología , Neoplasias Meníngeas/líquido cefalorraquídeo , Neoplasias Meníngeas/patología , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Rituximab
12.
Int J Hematol ; 78(3): 233-40, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14604282

RESUMEN

Expression of the Bcr-Abl oncoprotein alters various aspects of hematopoietic cells. We investigated the effects of a Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate, on the proliferation, adhesive properties, and morphology of a Bcr-Abl-transferred cell line, TF-1 Bcr-Abl, in comparison with parental TF-1. First, the factor-independent growth of TF-1 Bcr-Abl was inhibited in the presence of imatinib mesylate, but this inhibition was overcome by addition of exogenous granulocyte-macrophage colony-stimulating factor. Imatinib mesylate remarkably reduced tyrosine phosphorylation of Bcr-Abl, Cbl, and Crkl in a time-dependent manner, and their complex formation also was affected. Imatinib mesylate inhibited activation of Stat5 rather than the MEK-ERK1/2 pathway. TF-1 Bcr-Abl cells exhibited a round shape, unlike TF-1, and the adhesive property to fibronectin was much lower than that of TF-1. Although the Bcr-Abl oncoprotein may be involved negatively in cell adhesion, the decreased adhesion and altered morphology of TF-1 Bcr-Abl cells were minimally affected by imatinib mesylate and seemed independent of Bcr-Abl kinase activity. The present data indicated that the Bcr-Abl-specific kinase inhibitor cannot control Bcr-Abl-induced cell alterations other than autonomous growth.


Asunto(s)
Proteínas de Fusión bcr-abl , Proteínas de Fusión bcr-abl/fisiología , Leucemia Mieloide/patología , Proteínas de la Leche , Piperazinas/farmacología , Pirimidinas/farmacología , Benzamidas , Adhesión Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Tamaño de la Célula/efectos de los fármacos , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Proteína Oncogénica v-cbl , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-crk , Proteínas Oncogénicas de Retroviridae/metabolismo , Factor de Transcripción STAT5 , Transactivadores/antagonistas & inhibidores , Transfección
13.
J Biochem ; 134(3): 359-64, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-14561721

RESUMEN

We investigated the mechanism of apoptosis induced by bafilomycin A(1), an inhibitor of vacuolar H(+)-ATPase. Bafilomycin A(1) significantly inhibited the growth of MKN-1 human gastric cancer cells. Bafilomycin A(1) induced apoptosis as demonstrated by DNA ladder formation and the TUNEL method. We designed a flow cytometric assay to detect the alteration in lysosomal pH using a fluorescent probe, fluorescein isothiocyanate-conjugated dextran. This assay revealed that bafilomycin A(1) dramatically increased lysosomal pH. However, bafilomycin A(1) induced neither significant decrease in mitochondrial transmembrane potential nor the release of mitochondrial cytochrome c into the cytoplasm. Western blotting showed that cathepsin D, but not cathepsin L, was released into the cytoplasm. The activity of caspase-3 was significantly increased by bafilomycin A(1). However, cathepsin D did not directly cleave procaspase-3. These findings suggest that bafilomycin A(1)-induced apoptosis in MKN-1 cells is mediated by other proteases released after lysosomal dysfunction followed by activation of caspase-3 in a cytochrome c-independent manner. The present study showed that flow cytometric analysis of lysosomal pH can be useful to evaluate lysosomal protease-mediated apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Macrólidos/farmacología , Caspasa 3 , Caspasas/metabolismo , Catepsina D/metabolismo , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Humanos , Concentración de Iones de Hidrógeno , Etiquetado Corte-Fin in Situ , Lisosomas/metabolismo , ATPasas de Translocación de Protón/antagonistas & inhibidores
14.
Rinsho Ketsueki ; 44(5): 313-7, 2003 May.
Artículo en Japonés | MEDLINE | ID: mdl-12822405

RESUMEN

Chronic myeloid leukemia in a 61-year-old man progressed into the accelerated phase 8 months after the initial evaluation (Ph chromosome [20/20], FISH 93.5%), although the major cytogenetic response (Ph chromosome [0/20], FISH 9.7%) had been achieved 6 months after the initiation of the treatment with interferon and hydroxyurea. The Peripheral blood stem cells (Ph chromosome [0/20], FISH 5.8%, PCR 2.7 x 10(2) copies/microgram RNA) were harvested simultaneously with the attempt to induce the second chronic phase using the mini-ICE (idarubicin, cytosine arabinoside and etoposide) therapy. However, 2 months later, the disease progressed into blast crisis with the additional chromosomal abnormalities, and did not respond to the re-induction therapy with idarubicin and cytosine arabinoside. Autologous stem cell transplantation was then performed using the preparatory regimen with busulfan and cyclophosphamide. The third chronic phase was successfully achieved, and has been well maintained with imatinib for more than 13 months (Ph chromosome [0/20], FISH 0.0%, PCR < 10(2) copies/microgram RNA). This may be a rare case in which normal hematopoietic stem cells could be enriched in the peripheral blood in the accelerated phase, and that cytogenetic remission was achieved using these cells in the blast crisis. Flexible use of peripheral blood stem cells and imatinib could be an additional strategy for the better treatment of chronic myeloid leukemia.


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Trasplante de Células Madre de Sangre Periférica , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas , Terapia Combinada , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Inducción de Remisión , Trasplante Autólogo
15.
Biochem Biophys Res Commun ; 297(3): 664-71, 2002 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-12270146

RESUMEN

A human megakaryoblastic cell line, CMK, was treated with 12-o-tetradecanoylphorbol-13-acetate (TPA) for differentiation-induction. We examined TPA-induced activation of the MEK1-ERK1/2 pathway in the 100,000g Triton X-insoluble fraction of CMK cells as the membrane skeleton and researched the relation of the MEK1-ERK1/2 activation with integrin expression. We found that this activation was divided into two phases: the first activation occurred transiently in the membrane skeleton fraction of the suspended cell status and diminished after 1h; and the second sustained activation was maintained by cell adhesion. TPA-treated CMK cells revealed increased expression of integrins alphaIIb and beta3 only when the cell adhesion persisted, regardless of the difference of culture substratum. Sustained activation of the MEK1-ERK1/2 pathway is generated in the membrane skeleton by continuous cell adhesion and seems to be essential to TPA-induced megakaryocytic differentiation of CMK cells.


Asunto(s)
Adhesión Celular/fisiología , Diferenciación Celular/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Megacariocitos/enzimología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Butadienos/farmacología , Adhesión Celular/efectos de los fármacos , Membrana Celular/enzimología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Cinética , Leucemia , MAP Quinasa Quinasa 1 , Megacariocitos/citología , Megacariocitos/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos , Nitrilos/farmacología , Acetato de Tetradecanoilforbol/farmacología , Células Tumorales Cultivadas
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