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1.
Radiat Prot Dosimetry ; 182(1): 80-84, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30418654

RESUMO

The acute radiation syndrome (ARS) constitutes the most challenging, immediate medical consequence of exposure to high doses of ionizing radiation in an emergency situation. This report highlights some of the currently available medical guidelines and recommendations on the clinical management of ARS, comments recent trends regarding the approval of targeted pharmaceuticals for ARS, and suggests further initiatives for international collaboration aiming at continuously updating the medical knowledge base of this syndrome.


Assuntos
Síndrome Aguda da Radiação/prevenção & controle , Cooperação Internacional , Exposição à Radiação/efeitos adversos , Radiação Ionizante , Síndrome Aguda da Radiação/etiologia , Gerenciamento Clínico , Humanos
3.
Oncogene ; 36(32): 4619-4628, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28368400

RESUMO

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.


Assuntos
Mesilato de Imatinib/uso terapêutico , Interferon gama/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT1/metabolismo , Antígenos CD34/metabolismo , Linhagem Celular Tumoral , Humanos , Mesilato de Imatinib/farmacologia , Interferon gama/farmacologia , Leucaférese , Leucemia Mieloide de Fase Crônica/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteína Inibidora de Apoptose Neuronal/efeitos dos fármacos , Proteína Inibidora de Apoptose Neuronal/metabolismo , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Proteína de Morte Celular Associada a bcl/efeitos dos fármacos , Proteína de Morte Celular Associada a bcl/metabolismo
4.
Leukemia ; 31(5): 1108-1116, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27890936

RESUMO

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56bright NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.


Assuntos
Mesilato de Imatinib/uso terapêutico , Células Matadoras Naturais/citologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Estudos de Casos e Controles , Citocinas/metabolismo , Dasatinibe/uso terapêutico , Intervalo Livre de Doença , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Contagem de Linfócitos , Subpopulações de Linfócitos/citologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Suspensão de Tratamento
5.
Radiat Prot Dosimetry ; 171(1): 134-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27574328

RESUMO

The triple disaster in March 2011 tragically and severely affected the Japanese society, in spite of its well-developed infrastructure and good access to resources. A multitude of Japanese and international reports have since described the chain of events and actions taken in connection with the earthquake, the tsunami and the power plant failure in Fukushima. In order to further evaluate Japanese experiences of the disaster, and to bring home 'lessons-learnt' of relevance for continued emergency preparedness planning, a group from the National Board of Health and Welfare and other Swedish agencies performed an observer visit to Japan in 2012. A report from the group was recently published. Its main conclusions, and implications focusing on a strengthened national medical preparedness for radionuclear events in Sweden (and possibly elsewhere), are presented here.


Assuntos
Defesa Civil , Planejamento em Desastres/métodos , Acidente Nuclear de Fukushima , Desastres , Terremotos , Serviços Médicos de Emergência , Programas Governamentais , Humanos , Japão , Centrais Nucleares , Desenvolvimento de Programas , Lesões por Radiação , Suécia
6.
Radiat Prot Dosimetry ; 171(1): 144-55, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27521205

RESUMO

The World Health Organization (WHO) guideline development policy requires that WHO guidelines be developed in a manner that is transparent and based on all available evidences, which must be synthesised and formally assessed for quality. To fulfil this requirement, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach of rating quality of evidence and grading strength of recommendations was applied when developing the WHO recommendations on public health interventions in radiation emergencies. The guideline development group (GDG) formulated 10 PICO (P: population; I: intervention; C: comparator; O: outcomes) questions to guide the development of recommendations on response interventions during the early/intermediate and late emergency phases and on risk communications for mitigating psycho-social impact of radiation emergencies. For each PICO question, an extensive evidence search and systematic review was conducted. The GDG then formulated the recommendations using the evidence to recommendation (E-2-R) decision-making matrix and evaluated the strength of each recommendation.


Assuntos
Planejamento em Desastres/métodos , Liberação Nociva de Radioativos/prevenção & controle , Acidente Nuclear de Chernobyl , Comunicação , Tomada de Decisões , Desastres , Emergências , Exposição Ambiental , Medicina Baseada em Evidências , Feminino , Acidente Nuclear de Fukushima , Guias como Assunto , Humanos , Japão , Masculino , Centrais Nucleares , Exposição Ocupacional , Desenvolvimento de Programas , Saúde Pública , Garantia da Qualidade dos Cuidados de Saúde/normas , Medição de Risco , Ucrânia , Organização Mundial da Saúde
7.
Leukemia ; 30(9): 1853-60, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27133821

RESUMO

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 µg/week and it increased to 25 µg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Dasatinibe/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Interferon alfa-2 , Masculino , Pessoa de Meia-Idade , Derrame Pleural , Proteínas Recombinantes/administração & dosagem , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
8.
Leukemia ; 30(7): 1562-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27080811

RESUMO

We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.


Assuntos
Suscetibilidade a Doenças , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Neoplasias , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Prevalência , Sistema de Registros , Suécia/epidemiologia , Adulto Jovem
9.
Leukemia ; 27(7): 1520-6, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23328954

RESUMO

Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38-) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P=0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P=0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.


Assuntos
Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/patologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Dasatinibe , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
10.
Leukemia ; 25(10): 1587-97, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21647156

RESUMO

The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(-)CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-γ and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Divisão Celular , Citomegalovirus/fisiologia , Células Matadoras Naturais/citologia , Leucemia/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Tiazóis/efeitos adversos , Ativação Viral , Adulto , Idoso , Apoptose , Sequência de Bases , Primers do DNA , Dasatinibe , Feminino , Citometria de Fluxo , Humanos , Leucemia/imunologia , Leucemia/patologia , Leucemia/virologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
Leukemia ; 23(8): 1398-405, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19295545

RESUMO

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.


Assuntos
Antineoplásicos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Linfocitose/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Tiazóis/farmacologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Estudos de Coortes , Colite/induzido quimicamente , Dasatinibe , Feminino , Humanos , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Proteínas de Neoplasias/antagonistas & inibidores , Pleurisia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico
13.
Eur J Haematol ; 68(6): 376-81, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12225396

RESUMO

It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients 70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.


Assuntos
Aclarubicina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Tioguanina/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Taxa de Sobrevida , Fatores de Tempo
14.
Leuk Res ; 25(1): 13-18, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11137555

RESUMO

The outcome of continued EPO therapy was studied in 18 responding MDS patients. The EPO dose was reduced in a stepwise fashion to find the lowest possible maintenance dose. Relapses of anemia were associated with either progressive disease or reduction of the administered EPO dose. In the latter group second responses to renewed EPO therapy were readily achieved. Long-term responses were seen in about a third of the patients. Thus, it seems safe to reduce the EPO dose among responding patients. This approach may have advantages both from a medical and a socio-economic perspective.


Assuntos
Eritropoetina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/tratamento farmacológico , Relação Dose-Resposta a Droga , Eritropoetina/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Taxa de Sobrevida , Resultado do Tratamento
15.
J Clin Oncol ; 18(9): 1837-44, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10784624

RESUMO

PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment. PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography. RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp-negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed. CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Ciclosporinas/farmacologia , Daunorrubicina/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade
16.
Blood ; 95(4): 1456-64, 2000 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-10666225

RESUMO

Elevated leukotriene (LT)C(4) synthase activity was observed in peripheral blood granulocyte suspensions from patients with chronic myeloid leukemia (CML). Magnetic cell sorting (MACS) with CD16 monoclonal antibodies (mAbs), which were used to fractionate granulocytes from CML patients and healthy individuals, yielded highly purified suspensions of CD16(+) neutrophils. The purity of these cell fractions was verified by extensive morphologic examination. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses, demonstrating the absence of interleukin-4 messenger RNA (IL-4 mRNA), further confirmed the negligible contamination of eosinophils in these fractions. Notably, purified CML CD16(+) neutrophils from all tested patients transformed exogenous LTA(4) to LTC(4). These cells also produced LTC(4 )after activation with ionophore A23187 or the chemotactic peptide fMet-LeuPhe (N-formylmethionyl-leucyl-phenylalanine). Subcellular fractionation revealed that the enzyme activity was exclusively distributed to the microsomal fraction. Expression of LTC(4) synthase mRNA in CML CD16(+) neutrophils was confirmed by RT-PCR. Furthermore, Western blot analyses consistently demonstrated expression of LTC(4) synthase at the protein level in CML CD16(+) neutrophils, whereas expression of microsomal glutathione S-transferase 2 occurred occasionally. Expectedly, LTC(4) synthase activity or expression of the protein could not be demonstrated in CD16(+) neutrophil suspensions from any of the healthy individuals. Instead, these cells, as well as CML CD16(+) neutrophils, transformed LTA(4) to LTB(4). The results indicate that aberrant expression of LTC(4) synthase is a regular feature of morphologically mature CML CD16(+) neutrophils. This abnormality, possibly associated with malignant transformation, can lead to increased LTC(4) synthesis in vivo. Such overproduction may be of pathophysiological relevance because LTC(4 )has been demonstrated to stimulate proliferation of human bone marrow-derived myeloid progenitor cells. (Blood. 2000;95:1456-1464)


Assuntos
Glutationa Transferase/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Neutrófilos/enzimologia , Receptores de IgG/sangue , Antígenos CD/sangue , Ácido Araquidônico/farmacologia , Calcimicina/farmacologia , Glutationa Transferase/genética , Granulócitos/citologia , Granulócitos/enzimologia , Granulócitos/patologia , Humanos , Separação Imunomagnética , Interleucina-4/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucotrienos/sangue , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/citologia , Neutrófilos/patologia , RNA Mensageiro/genética , Frações Subcelulares/enzimologia , Transcrição Gênica
17.
Lakartidningen ; 97(3): 164-7, 2000 Jan 19.
Artigo em Sueco | MEDLINE | ID: mdl-10687346

RESUMO

The use of monoclonal antibodies (mabs) in cancer therapy has gained renewed interest, due to recent reports of remarkable clinical response, particularly in patients with low-grade non-Hodgkin lymphoma. Better defined and more appropriate target antigens and "humanized" mabs, reducing the risk of inducing neutralising human anti-mouse antibodies, have contributed to the improvement in results. Conjugation of mabs with various radionuclides is now being explored as a means of further enhancing clinical efficacy, the idea being to allow systemic delivery of targeted radiation to areas of disease while sparing normal tissue. Radioimmunotherapy may be administered as a single large dose of radiolabelled mabs, usually requiring haematological stem cell support, or as multiple, smaller fractions. The criteria for the selection of mabs and radionuclides are discussed in the article, as are recent clinical data and the problems and prospects of future developments in radioimmunotherapy.


Assuntos
Radioimunoterapia , Ensaios Clínicos como Assunto , Humanos , Radioimunoterapia/métodos , Radioimunoterapia/normas , Radioimunoterapia/tendências
18.
J Leukoc Biol ; 64(2): 228-34, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9715263

RESUMO

The expression of neurotrophin and neurotrophin receptor mRNAs in human granulocytes and bone marrow cells was examined using ribonuclease protection assay and reverse transcription-polymerase chain reaction. The granulocytes expressed mRNA coding for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3). Moreover, the inflammatory mediator leukotriene B4 (LTB4) up-regulated the expression of NT-4 mRNA in granulocytes, but did not affect the expression of other neurotrophin mRNAs. Granulocytes generally lacked expression of mRNA coding for neurotrophin receptors. In contrast, human bone marrow cells consistently expressed mRNA for trkB (the BDNF and NT-4 receptor) and displayed variable expression of mRNA coding for trkA (the tyrosine kinase NGF receptor) and LNGFR (the low-affinity NGF receptor), whereas mRNA for trkC (the NT-3 receptor) was not expressed. Contrary to granulocytes, normal bone marrow cells generally expressed only low levels of mRNA encoding BDNF and NT-4. Expression of mRNA encoding NGF and NT-3 was not detected. However, significantly increased expression of BDNF mRNA was observed when bone marrow cells from patients with chronic myeloproliferative disorders (MPD) were analyzed. The results suggest that neurotrophins may act as granulocyte-derived effector molecules and that human bone marrow cells may be targets for these compounds, in particular BDNF and NT-4.


Assuntos
Células da Medula Óssea/química , Granulócitos/química , Leucotrieno B4/farmacologia , Transtornos Mieloproliferativos/imunologia , Fatores de Crescimento Neural/genética , Células da Medula Óssea/imunologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/imunologia , Doença Crônica , Expressão Gênica/imunologia , Granulócitos/imunologia , Humanos , Leucotrieno B4/imunologia , Fatores de Crescimento Neural/imunologia , Fármacos Neuroprotetores/imunologia , Neurotrofina 3 , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/imunologia , Receptor do Fator Neutrófico Ciliar , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/imunologia , Regulação para Cima/imunologia
19.
Br J Haematol ; 101(4): 728-36, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9674747

RESUMO

Leukotrienes (LT) are inflammatory mediators which can also exert regulatory effects on human myelopoiesis. We have studied the LT-producing capacity of freshly isolated leucocyte suspensions (containing blast cells in variable proportions) from 41 patients with acute myeloid leukaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc) at diagnosis or relapse/resistant disease. Leucocyte suspensions from 19/29 AML patients (66%), and 2/12 CMLbc patients (17%; P = 0.012) demonstrated deficient capacity to synthesize LT from endogenous substrate after ionophore A23187 stimulation. Thus, these cells produced < 8 pmol LTB4+LTC4/10(6) cells (< 20% of mean LT formation in leucocyte suspensions from 18 healthy subjects). Addition of exogenous arachidonic acid did not normalize the LT synthesis in poor-producing cell suspensions. Purified, morphologically mature granulocytes from two AML patients also failed to produce normal amounts of LT. In leucocyte suspensions from the remaining 20 AML/CMLbc patients A23187 provoked LT biosynthesis, with markedly increased production of LTC4, but decreased LTB4 formation. Furthermore, elevated conversion of exogenous LTA4 to LTC4 was noted in the patient samples, independent of their capacity to produce LT after A23187 stimulation. The percentage of blast cells in patient white blood cell differential counts correlated inversely with ionophore-induced LT synthesis, but positively with the conversion of exogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.


Assuntos
Crise Blástica/enzimologia , Glutationa Transferase/metabolismo , Leucemia Mieloide/enzimologia , Leucócitos/enzimologia , Leucotrienos/biossíntese , Doença Aguda , Adolescente , Adulto , Idoso , Feminino , Granulócitos/enzimologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucotrieno A4/biossíntese , Leucotrieno A4/deficiência , Leucotrieno C4/biossíntese , Leucotrieno C4/deficiência , Leucotrienos/deficiência , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
20.
Eur J Haematol ; 58(4): 241-5, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9186534

RESUMO

We have employed fluorescence in situ hybridization (FISH) in combination with standard morphology (MGG/FISH) to identify the clonal involvement of different bone marrow cell lineages in 20 AML patients (14 MDS-AML, 6 de novo AML). Even though the number of cells belonging to the abnormal clone varied between individual cases, the percentage of clonal blasts was similar in MDS-AML and de novo AML patients. The erythropoietic cells appeared to be part of the abnormal clone in 13 of 14 patients with MDS-AML, but only in 1 of 6 with de novo AML. Similarly, clonal granulocytes were detected in 13 of 14 patients with MDS-AML, compared to 2 of 6 with de novo AML. Lymphocytes consistently displayed normal, diploid karyotype. The results suggest that it is possible to distinguish between MDS-AML and de novo AML by the use of MGG/FISH; in de novo AML the abnormal chromosomal clone is generally confined to the immature myeloid cells, while in MDS-AML mature granulocytes and erythroid cells are of clonal origin. It is, however, not possible to conclude that MDS-AML is a "multipotent" type of leukaemia, since it cannot be ruled out that the chromosomally aberrant erythroid cells and granulocytes represent surviving cells from the original MDS clone.


Assuntos
Medula Óssea/patologia , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 7 , Feminino , Granulócitos/patologia , Humanos , Hibridização in Situ Fluorescente , Interfase , Cariotipagem , Leucemia Monocítica Aguda/sangue , Leucemia Monocítica Aguda/classificação , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue
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