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1.
Leukemia ; 19(6): 930-5, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15815726

RESUMO

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC(50)<1 vs 3-10 nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.


Assuntos
Leucemia Mieloide/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Quinolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Ureia/análogos & derivados , Ureia/farmacologia , Doença Aguda , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Proteínas do Leite/metabolismo , Mutação , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Quinolinas/química , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT5 , Transativadores/metabolismo , Ureia/química , Tirosina Quinase 3 Semelhante a fms
2.
J Thromb Haemost ; 3(2): 355-60, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15670044

RESUMO

Previous in vitro studies demonstrated that thrombopoietin (TPO) acts on platelets to activate a variety of intracellular signaling pathways and to enhance platelet sensitivity to multiple agonists. Little is known, however, about whether TPO exerts prothrombotic effects in vivo. The aim of this study was to examine the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a pegylated N-terminal domain of human TPO, in a rat model of venous thrombosis. A microthrombus was photochemically induced on the vessel wall of a mesenteric venule, but the vessel was not occluded by it. A single intravenous injection of PEG-rHuMGDF (3 microg kg(-1)) after the thrombus generation into normal rats enhanced the thrombus size, resulting in transient thrombotic occlusion in the majority of rats. Stimulatory effects on thrombus growth were also observed following administration of glycosylated recombinant human full-length TPO (6 microg kg(-1)). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 microg kg(-1), did not induce a significant increase in thrombus size or thrombotic occlusion. Platelets from thrombocytopenic rats had decreased surface levels of c-Mpl and decreased sensitivity to PEG-rHuMGDF in an in vitro aggregation response. Thus, decreased prothrombotic effects of PEG-rHuMGDF in thrombocytopenic rats might be the result not only of low platelet counts but also of decreased platelet reactivity to PEG-rHuMGDF. These results indicate that PEG-rHuMGDF has little effect on venous thrombus formation in thrombocytopenic states associated with high endogenous TPO levels.


Assuntos
Polietilenoglicóis/farmacologia , Proteínas Recombinantes/farmacologia , Trombocitopenia/complicações , Trombofilia/induzido quimicamente , Trombopoetina/farmacologia , Trombose/induzido quimicamente , Animais , Plaquetas/patologia , Citocinas/farmacologia , Modelos Animais de Doenças , Humanos , Agregação Plaquetária/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Ratos , Proteínas Recombinantes/administração & dosagem , Trombopoetina/administração & dosagem , Trombopoetina/sangue , Trombopoetina/fisiologia
3.
Thromb Haemost ; 85(1): 152-9, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11204567

RESUMO

Thrombopoietin (TPO), or megakaryocyte growth and development factor (MGDF), has been shown to potentiate the sensitivity of normal human platelets to various agonists in vitro. The present study investigated the functional and biochemical properties of platelets from mice rendered thrombocytopenic by sublethal irradiation with regard to the reactivity to recombinant murine MGDF (rmMGDF) in vitro. During the course of reversible thrombocytopenia following irradiation, platelets from irradiated mice which had lower platelet counts and reciprocally higher plasma TPO levels showed lower reactivity to rmMGDF in agonist-induced platelet aggregation. Intravenous injections of recombinant soluble murine c-Mpl (sMpl), which has the ability to capture TPO, after irradiation restored the reactivity of platelets at the platelet nadir to rmMGDF. On the other hand, platelets prepared from normal mice 3 h after a single intravenous injection of pegylated rmMGDF did not respond to rmMGDF. There was a marked decrease in c-Mpl and Janus kinase 2 (JAK2) in platelets from irradiated mice at the platelet nadir. Similar results were observed with platelets from mice administered pegylated rmMGDF. JAK2 was only moderately decreased, however, in platelets from mice given sMpl after irradiation. These results indicate that exposure of platelets to increased endogenous TPO levels in vivo in thrombocytopenic mice leads to a reduction in the platelet reactivity to rmMGDF in vitro. Further, these results suggest that the c-Mpl-mediated signaling pathway, which is essential for the priming effect of rmMGDF, is defective in thrombocytopenic murine platelets.


Assuntos
Plaquetas/efeitos dos fármacos , Proteínas de Neoplasias , Receptores de Citocinas , Trombopoetina/farmacologia , Animais , Plaquetas/fisiologia , Plaquetas/efeitos da radiação , Divisão Celular/efeitos dos fármacos , Divisão Celular/efeitos da radiação , Modelos Animais de Doenças , Janus Quinase 2 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos da radiação , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/administração & dosagem , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/farmacologia , Receptores de Trombopoetina , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/fisiologia , Trombocitopenia/metabolismo , Trombocitopenia/fisiopatologia , Trombopoetina/metabolismo , Trombopoetina/efeitos da radiação
4.
Biosci Biotechnol Biochem ; 60(1): 103-7, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8824829

RESUMO

Tautomycin, a protein serine/threonine phosphatase inhibitor, was chemically degraded, and five derivatives were investigated for their biological activities. None of them exerted any inhibitory effects on the activity of protein phosphatase types 1 and 2A. However, one derivative, named TM2a, induced a significant morphological change (bleb-formation) of human myeloid leukemia K562 cells. TM2b, the trimethyl ester of TM2, did not induce bleb-formation. Thus, the maleic anhydride structure played an important role in the biological activity. The biological properties of TM2a toward K562 cells resembled those of a phorbol ester, rather than of tautomycin. The phorbol ester-induced bleb formation was abrogated by a non-specific inhibitor of protein kinases, staurosporine, and by an inhibitor of protein kinase C (PKC), H-7, but TM2a-induced bleb formation was abrogated only by staurosporine. Enhanced phosphorylation of the two proteins was observed after their exposure to TM2a. This suggest that the effect was not due to any inhibition of protein phosphatase 1 or 2A, but rather to the activation of an unidentified kinase, possibly of the PKC family, or to inhibition of a protein phosphatase other than type 1 or 2A.


Assuntos
Leucemia Mieloide/patologia , Inibidores da Agregação Plaquetária/metabolismo , Piranos , Compostos de Espiro , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Biodegradação Ambiental , Humanos , Ésteres de Forbol/metabolismo , Ésteres de Forbol/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Fosforilação , Proteína Fosfatase 1 , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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