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1.
Am J Chin Med ; 47(1): 223-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30630343

RESUMO

Casticin, derived from Fructus Viticis, has anticancer properties in many human cancer cells, however, there is no report to show that casticin promotes immune responses and affects the survival rate of leukemia mice in vivo. The aim of this study is to evaluate the effects of casticin on immune responses and the survival rate of WEHI-3 cells generated in leukemia mice in vivo. Animals were divided into six groups: normal control mice, leukemia control mice, mice treated with ATRA (all-trans retinoic acid), and casticin (0.1, 0.2, and 0.4 mg/kg) treated mice. All animals were treated for 14 days and then measured for body weights, total survival rate, cell markers, the weights of liver and spleen, phagocytosis of spleen cells, NK cell activities and cell proliferation. Results show that casticin did not affect animal appearances, however, it increased body weights and decreased the weights of liver at 0.2 mg/kg and 0.4 mg/kg treatment. Casticin also decreased spleen weight at 0.2 mg/kg and 0.4 mg/kg treatment, increased CD3 at 0.1, 0.2 and 0.4 mg/kg doses and increased CD19 at 0.2 mg/kg treatment but decreased CD11b and Mac-3 at 0.1, 0.2 and 0.4 mg/kg treatment. Casticin (0.1, 0.2 and 0.4 mg/kg) increased macrophage phagocytosis from PBMC (peripheral blood mononuclear cell) and peritoneal cavity. Furthermore, casticin increased NK cells' cytotoxic activity and promoted T cell proliferation at 0.1-0.4 mg/kg treatment with or without concanavalin A (Con A) stimulation, but only increased B cell proliferation at 0.1 mg/kg treatment. Based on these observations, casticin could be used as promoted immune responses in leukemia mice in vivo.


Assuntos
Antineoplásicos Fitogênicos , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Células Matadoras Naturais/imunologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/imunologia , Macrófagos/imunologia , Fagocitose/efeitos dos fármacos , Fitoterapia , Animais , Flavonoides/isolamento & purificação , Humanos , Leucemia Mielomonocítica Aguda/mortalidade , Masculino , Camundongos Endogâmicos BALB C , Estimulação Química , Taxa de Sobrevida , Células Tumorais Cultivadas , Vitex/química
2.
Exp Hematol ; 68: 66-79.e3, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208330

RESUMO

The selection of chemotherapy regimen for elderly patients with acute myeloid leukemia (AML) remains challenging. Here, we report that granulocyte colony-stimulating factor (G-CSF) upregulates the expression of microRNA (miR)-146a in a nuclear factor kappaB-dependent manner, leading to direct decreases in the expression of the target proteins CXCR4 and Smad4 in AML cells in vitro. The reduction in CXCR4 expression suppressed the migration abilities of leukemia cells. Downregulation of Smad4 promoted cell cycle entry in leukemia cells. Furthermore, an increase in apoptosis was observed when leukemia cells were treated sequentially with G-CSF and cytosine arabinoside in vitro. These findings suggest that G-CSF treatment may disrupt the protection of bone marrow niches from leukemia cells. In a review of data from 78 cases of primary AML, we found that a high miR-146a expression and/or upregulation of this miRNA during G-CSF priming chemotherapy was predictive of better clinical outcomes. Our findings suggest that miR-146a may be a novel biomarker for evaluating the clinical prognosis and treatment effects of a G-CSF priming protocol in elderly patients with AML.


Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , MicroRNAs/fisiologia , RNA Neoplásico/fisiologia , Aclarubicina/administração & dosagem , Aclarubicina/efeitos adversos , Aclarubicina/farmacologia , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiotaxia/efeitos dos fármacos , Técnicas de Cocultura , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Células HL-60 , Humanos , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Prognóstico , Interferência de RNA , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Receptores CXCR4/biossíntese , Receptores CXCR4/genética , Proteína Smad4/biossíntese , Proteína Smad4/genética , Nicho de Células-Tronco , Microambiente Tumoral , Regulação para Cima/efeitos dos fármacos
3.
Am J Manag Care ; 24(16 Suppl): S356-S365, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30132679

RESUMO

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that largely impacts the elderly population. Not all AML patients are candidates for the mainstay induction and consolidation treatment options. In addition, despite available therapies, most patients will eventually relapse on, or be refractory to, standard induction therapy, with limited subsequent choices and poor prognosis. Recently, several new and emerging therapies, with a variety of mechanisms of action, have broadened the treatment landscape in newly diagnosed and relapsed/refractory (R/R) AML, providing patients and healthcare providers with more options and several targeted treatment approaches. Preclinical data indicate that the anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) is important to AML cell survival. Cyclin-dependent kinase 9 (CDK9), a transcriptional activator necessary for the expression of MCL-1, represents a promising target for future AML therapies. A number of CDK9 inhibitors, as well as several direct MCL-1 inhibitors, are currently in clinical or preclinical development. The CDK9 inhibitors alvocidib, atuveciclib, and TG02 have completed phase 1/2 clinical trials, with results available for the alvocidib trial showing improved complete remission rates (70% vs 46%; P = .003) for alvocidib in combination with cytarabine and mitoxantrone, versus cytarabine/daunorubicin, in patients with newly diagnosed AML. In addition, several phase 1 clinical trials with CDK9 inhibitors are currently recruiting for treatment of advanced AML. A phase 1b study is also ongoing to investigate alvocidib in combination with B-cell lymphoma-2 inhibitor venetoclax for R/R AML. Although further research is needed, CDK9 inhibitors represent a promising new approach for the treatment of AML.


Assuntos
Leucemia Mielomonocítica Aguda/tratamento farmacológico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Compostos de Piridínio/uso terapêutico , Sulfonamidas/uso terapêutico , Triazinas/uso terapêutico
7.
Pediatr Blood Cancer ; 62(9): 1664-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25855531

RESUMO

Childhood acute myeloid leukaemia (AML) requires intensive therapy and is associated with survival rates that are substantially inferior to many other childhood malignancies. We undertook a retrospective analysis of Australian Paediatric Cancer Registry data from 1997 to 2008 together with a single-centre audit during the same period assessing burden on service delivery at a tertiary children's hospital (Royal Children's Hospital, Brisbane). Although survival improved from 54.3% (1997-2002) to 69.2% (2003-2008), childhood AML caused a disproportionate number of childhood cancer deaths, accounting for 5.5% of all childhood cancer diagnoses yet 7.9% of all childhood cancer mortality. Furthermore, treatment was associated with significant toxicity requiring intensive use of local health resources. Novel therapeutic strategies aimed at improving survival and reducing toxicity are urgently required.


Assuntos
Recursos em Saúde/estatística & dados numéricos , Leucemia Mieloide Aguda/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália/epidemiologia , Criança , Pré-Escolar , Terapia Combinada , Efeitos Psicossociais da Doença , Infecção Hospitalar/epidemiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/epidemiologia , Leucemia Mielomonocítica Aguda/terapia , Masculino , Infecções Oportunistas/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Centros de Atenção Terciária/estatística & dados numéricos , Resultado do Tratamento
8.
Ann Hematol ; 94(2): 211-21, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25241285

RESUMO

Recently, mutations of the GATA binding protein 2 (GATA2) gene were identified in acute myeloid leukemia (AML) patients with CEBPA double mutations (CEBPA (double-mut)), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, 14 different missense GATA2 mutations, which were all clustered in the highly conserved N-terminal zinc finger 1 domain, were identified in 27.4, 6.7, and 1 % of patients with CEBPA (double-mut), CEBPA (single-mut), and CEBPA wild type, respectively. All but one patient with GATA2 mutation had concurrent CEBPA mutation. GATA2 mutations were closely associated with younger age, FAB M1 subtype, intermediate-risk cytogenetics, expression of HLA-DR, CD7, CD15, or CD34 on leukemic cells, and CEBPA mutation, but negatively associated with FAB M4 subtype, favorable-risk cytogenetics, and NPM1 mutation. Patients with GATA2 mutation had significantly better overall survival and relapse-free survival than those without GATA2 mutation. Sequential analysis showed that the original GATA2 mutations might be lost during disease progression in GATA2-mutated patients, while novel GATA2 mutations might be acquired at relapse in GATA2-wild patients. In conclusion, AML patients with GATA2 mutations had distinct clinic-biological features and a favorable prognosis. GATA2 mutations might be lost or acquired at disease progression, implying that it was a second hit in the leukemogenesis of AML, especially those with CEBPA mutation.


Assuntos
Fator de Transcrição GATA2/genética , Leucemia Mieloide/genética , Mutação , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Aberrações Cromossômicas , Progressão da Doença , Seguimentos , Genótipo , Humanos , Estimativa de Kaplan-Meier , Cariótipo , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patologia , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Adulto Jovem
9.
Ann Hematol ; 93(10): 1695-703, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24824767

RESUMO

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.


Assuntos
Medula Óssea/patologia , Linhagem da Célula , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Núcleo Celular/ultraestrutura , Citoplasma/ultraestrutura , Análise Mutacional de DNA , Feminino , Hematopoese , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/mortalidade , Leucemia Mielomonocítica Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Risco , Adulto Jovem
10.
Saudi Med J ; 35(4): 346-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24749130

RESUMO

OBJECTIVE: To establish the benefits of immature reticulocyte fraction (IRF) measurement using an automated hematology cells analyzer over absolute neutrophil count (ANC) in predicting bone marrow recovery post induction chemotherapy. METHODS: A prospective observational study was carried out in the Departments of Pathology, Medicine, and Pediatrics, Universiti Kebangsaan Malaysia, Medical Center (UKMMC), Kuala Lumpur, Malaysia during a period of 19 months from April 2009 to December 2010 to assess the bone marrow recovery in patients with acute leukemia. A total of 22 patients in remission induction phases were enrolled in this study. The blood specimens were collected from day zero after chemotherapy, and every 3 days until patients recovered hematologically. All blood samples were measured for ANC and IRF using an automated hematology analyzer (Beckman-Coulter LH750). RESULTS: The percentage of patients showing IRF recovery earlier than ANC recovery was 63.6% (14 out of 22 patients). There was a significant difference in the mean number of days for IRF recovery as compared with ANC recovery (14.05 and 17.18 days), p=0.005. CONCLUSION: This study proved that IRF was more useful in predicting bone marrow recovery in a patient with acute leukemia post induction chemotherapy compared with ANC. The IRF is not affected by infection, is easily measured, and inexpensive; thus, it is a reliable parameter to evaluate bone marrow reconstitution.


Assuntos
Medula Óssea/fisiopatologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Reticulócitos/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mielomonocítica Aguda/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Estudos Prospectivos , Indução de Remissão , Contagem de Reticulócitos , Adulto Jovem
11.
Int J Cancer ; 135(6): 1497-508, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-24523193

RESUMO

CMML (chronic myelomonocytic leukemia) belongs to the group of myeloid neoplasms known as myelodysplastic and myeloproliferative diseases. In some patients with a history of CMML, the disease transforms to acute myelomonocytic leukemia (AMML). There are no specific treatment options for patients suffering from CMML except for supportive care and DNA methyltransferase inhibitors in patients with advanced disease. New treatment strategies are urgently required, so we have investigated the use of immunotherapeutic directed cytolytic fusion proteins (CFPs), which are chimeric proteins comprising a selective domain and a toxic component (preferably of human origin to avoid immunogenicity). The human serine protease granzyme B is a prominent candidate for tumor immunotherapy because it is expressed in cytotoxic T lymphocytes and natural killer cells. Here, we report the use of CD64 as a novel target for specific CMML and AMML therapy, and correlate CD64 expression with typical surface markers representing these diseases. We demonstrate that CD64-specific human CFPs kill CMML and AMML cells ex vivo, and that the mutant granzyme B protein R201K is more cytotoxic than the wild-type enzyme in the presence of the granzyme B inhibitor PI9. Besides, the human CFP based on the granzyme B mutant was also able to kill AMML or CMML probes resistant to Pseudomonas exotoxin A.


Assuntos
Granzimas/administração & dosagem , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estabilidade de Medicamentos , Feminino , Células HL-60 , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/sangue , Imunotoxinas/imunologia , Imunotoxinas/farmacocinética , Leucemia Mielomonocítica Aguda/imunologia , Leucemia Mielomonocítica Crônica/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de IgG/biossíntese , Receptores de IgG/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/sangue , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacocinética , Anticorpos de Cadeia Única/administração & dosagem , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacocinética
12.
Am J Hematol ; 89(4): 399-403, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24375467

RESUMO

Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥ 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard-dose cytarabine (200 mg/m² /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Salvação , Idoso , Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Ensaios de Uso Compassivo , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Proteínas Recombinantes/uso terapêutico , Indução de Remissão , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente
16.
Blood ; 122(20): 3432-9, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24092933

RESUMO

This trial tested the safety and efficacy of a regimen consisting of hydroxyurea followed by azacitidine, 75 mg/m(2) for 7 days, and gemtuzumab ozogamicin, 3 mg/m(2) on day 8, in older patients with newly diagnosed acute myeloid leukemia. Those achieving a complete remission received 1 consolidation treatment followed by 4 cycles of azacitidine. The patients were stratified into good-risk (age 60-69 years or performance status 0-1) and poor-risk (age ≥70 years and performance status 2 or 3) groups. Specific efficacy and safety goals were defined as being supportive of further study of the regimen. Eighty-three patients were registered in the good-risk cohort and 59 in poor-risk cohort, with median age of 71 and 75 years, respectively. In the good-risk group, 35 patients (44%) achieved a complete remission. Median relapse-free and overall survivals were 8 and 11 months, respectively. Six patients (8%) died within 30 days of registration. In the poor-risk group, 19 (35%) achieved a complete remission. Median relapse-free and overall survivals were 7 and 11 months, respectively. Seven patients (14%) died early. The results of this trial met predefined goals for efficacy and safety for the poor-risk cohort but not the good-risk group. .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Risco , Análise de Sobrevida
17.
Blood ; 122(20): 3521-32, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24014241

RESUMO

Cancer cells require nutrients and energy to adapt to increased biosynthetic activity, and protein synthesis inhibition downstream of mammalian target of rapamycin complex 1 (mTORC1) has shown promise as a possible therapy for acute myeloid leukemia (AML). Glutamine contributes to leucine import into cells, which controls the amino acid/Rag/mTORC1 signaling pathway. We show in our current study that glutamine removal inhibits mTORC1 and induces apoptosis in AML cells. The knockdown of the SLC1A5 high-affinity transporter for glutamine induces apoptosis and inhibits tumor formation in a mouse AML xenotransplantation model. l-asparaginase (l-ase) is an anticancer agent also harboring glutaminase activity. We show that l-ases from both Escherichia coli and Erwinia chrysanthemi profoundly inhibit mTORC1 and protein synthesis and that this inhibition correlates with their glutaminase activity levels and produces a strong apoptotic response in primary AML cells. We further show that l-ases upregulate glutamine synthase (GS) expression in leukemic cells and that a GS knockdown enhances l-ase-induced apoptosis in some AML cells. Finally, we observe a strong autophagic process upon l-ase treatment. These results suggest that l-ase anticancer activity and glutamine uptake inhibition are promising new therapeutic strategies for AML.


Assuntos
Glutamina/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Sistema ASC de Transporte de Aminoácidos/antagonistas & inibidores , Sistema ASC de Transporte de Aminoácidos/genética , Animais , Apoptose/efeitos dos fármacos , Asparaginase/isolamento & purificação , Asparaginase/farmacologia , Autofagia/efeitos dos fármacos , Proteínas de Bactérias/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Escherichia coli/farmacologia , Feminino , Glutaminase/isolamento & purificação , Glutaminase/farmacologia , Glutamina/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor , Complexos Multiproteicos/antagonistas & inibidores , Pectobacterium chrysanthemi/enzimologia , Biossíntese de Proteínas/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
18.
Br J Haematol ; 163(3): 315-25, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24033280

RESUMO

Evidence regarding the efficacy of gemtuzumab ozogamicin (GO) addition to standard induction chemotherapy in newly diagnosed acute myeloid leukaemia (AML) is conflicting. This systematic review aimed to identify and summarize all evidence regarding the benefits and harms of adding GO to conventional chemotherapy for induction treatment of AML. A comprehensive literature search of two databases (PUBMED and Cochrane) from inception up to November 22, 2012, and 4 years of proceedings from four major haematology/oncology conferences was undertaken. Endpoints included benefits (complete remission, relapse-free, event-free, and overall survival), and harms (early mortality and incidence of hepatic veno-occlusive disease/sinusoidal obstructive syndrome). Seven trials (3942 patients) met all inclusion criteria. Addition of GO showed improved relapse-free [Hazard Ratio (HR) = 0·84 (95% confidence interval (CI) 0·71-0·99)] and event-free survival [HR = 0·59 (95%CI 0·48-0·74)] but not overall survival [HR = 0·95 (95%CI 0·83-1·08)]. Addition of GO resulted in higher rate of early mortality [Risk Ratio = 1·60 (95%CI 1·07-2·39)]. Improved overall survival was observed in studies using a lower cumulative GO dose (<6 mg/m(2) ) [HR = 0·89 (95%CI 0·81-0·99)]. Addition of GO to conventional chemotherapy as induction therapy may improve relapse-free and event-free survival, but does not impact overall survival and significantly increases early mortality in AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Medicina Baseada em Evidências , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/epidemiologia , Humanos , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Indução de Remissão , Retirada de Medicamento Baseada em Segurança , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
19.
Intern Med ; 52(11): 1217-21, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23728559

RESUMO

Although fatal pulmonary complications frequently occur during the course of acute leukemia, a minor proportion of the complications are due to leukemia itself. Infections, drug reactions and concomitant medical conditions are the major causes of respiratory distress in leukemic patients. We treated four patients with acute myeloid leukemia complicated by leukemic cell lysis pneumopathy (LCLP). All of the patients had leukemia of monocytoid origin and their respiratory function deteriorated soon after chemotherapy initiation. Although two of the patients required mechanical ventilation, all four improved after continued chemotherapy. Our experience indicates that, in cases of LCLP, chemotherapy should be continued with maximal respiratory support.


Assuntos
Leucemia Monocítica Aguda/diagnóstico , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Infiltração Leucêmica/diagnóstico , Infiltração Leucêmica/tratamento farmacológico , Adolescente , Idoso , Morte Celular/fisiologia , Feminino , Humanos , Leucemia Monocítica Aguda/sangue , Leucemia Mielomonocítica Aguda/sangue , Infiltração Leucêmica/sangue , Masculino , Pessoa de Meia-Idade
20.
Int J Hematol ; 97(5): 657-66, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23605368

RESUMO

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare tumor derived from interdigitating dendritic cells. We report the first case of a 64-year-old Chinese woman who was diagnosed with simultaneous IDCS and acute myelomonocytic leukemia (AML-M4). The patient had undergone chemotherapy for breast cancer 6 years previously. Based on the laboratory results, both the IDCS and the AML-M4 in this patient were determined to be of myelogenous origination. Furthermore, a review of 62 IDCS cases (Medline database, key word: IDCS) reported to date revealed that as many as 17 % of the patients had malignant disease and received radiotherapy and/or chemotherapy prior to developing IDCS, and that this group of patients showed worse prognosis compared with counterparts. The patient in the present report showed poor response to four cycles of sequential chemotherapy, and died 6 months after the initial diagnosis.


Assuntos
Sarcoma de Células Dendríticas Interdigitantes/complicações , Leucemia Mielomonocítica Aguda/complicações , Biópsia , Sarcoma de Células Dendríticas Interdigitantes/diagnóstico , Sarcoma de Células Dendríticas Interdigitantes/tratamento farmacológico , Evolução Fatal , Feminino , Humanos , Imuno-Histoquímica , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucossialina/metabolismo , Linfonodos/patologia , Pessoa de Meia-Idade
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