RESUMO
The active components in cloves are eugenol and isoeugenol. Eugenol has recently become a focus of interest because of its potential role in alleviating and preventing chronic diseases such as cancer, inflammatory reactions, and other conditions. The radical-scavenging and anti-inflammatory activities of eugenol have been shown to modulate chronic diseases in vitro and in vivo, but in humans, the therapeutic use of eugenol still remains to be explored. Based on a review of the recent literature, the antioxidant, anti-proliferative, and anti-inflammatory activities of eugenol and its related compounds are discussed in relation to experimentally determined antioxidant activity (stoichiometric factor n and inhibition rate constant) and theoretical parameters [phenolic O-H bond dissociation enthalpy (BDE), ionization potential (IP according to Koopman's theorem), and electrophilicity (ω)], calculated using a density functional theory method. Dimers of eugenol and its related compounds showed large antioxidant activities and high ω values and also exerted efficient anti-inflammatory activities. Eugenol appears to possess multiple antioxidant activities (dimerization, recycling, and chelating effect) in one molecule, thus having the potential to alleviate and prevent chronic diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Doença Crônica/tratamento farmacológico , Descoberta de Drogas/métodos , Eugenol/uso terapêutico , Syzygium/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Modelos Animais de Doenças , Eugenol/química , Eugenol/isolamento & purificação , Humanos , Estrutura Molecular , Fitoterapia , Plantas Medicinais , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Amoebiasis has rarely been reported in patients undergoing hematopoietic stem cell transplantation, although it is a world-wide infection and extremely common. We present a case of intestinal amoebiasis unexpectedly revealed by colonoscopy after allogeneic bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor for acute myeloid leukemia arising from chronic myelomonocytic leukemia and successfully treated by metronidazole.
Assuntos
Antiprotozoários/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Disenteria Amebiana/tratamento farmacológico , Doença Enxerto-Hospedeiro/complicações , Metronidazol/uso terapêutico , Disenteria Amebiana/etiologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-IdadeRESUMO
Recent studies have suggested that intrauterine undernutrition is closely associated with the pathogenesis of diseases after birth. Perinatal undernutrition is known to disturb the development of reproductive function and delay the onset of puberty in some species. Using a rat model, we determined the effects of prenatal undernutrition on the development of the hypothalamic kisspeptin system and evaluated whether the alteration of the kisspeptin system contributes to the delayed onset of puberty induced by prenatal undernutrition. We also evaluated the effects of prenatal undernutrition on the developmental changes in serum leptin levels because leptin was a putative positive regulator of the hypothalamic kisspeptin system. We compared the timing of vaginal opening (VO) and the developmental changes in body weight, hypothalamic Kiss1 mRNA levels, and serum leptin concentrations between offspring with prenatal undernutrition (UN offspring) and normal nutrition (NN offspring). After birth, the UN offspring showed rapid growth and had caught up to body weight of the NN offspring by postnatal day 12. After postnatal day 16, the UN offspring showed significantly lower Kiss1 mRNA levels than the NN offspring, despite their significantly higher serum leptin levels (at days 20 and 28). The timing of VO in the UN offspring was delayed compared with that in the NN offspring, and chronic central injection of kisspeptin normalized the timing of VO in the UN offspring. These results suggest that decreased hypothalamic kisspeptin action contributes to the delayed onset of puberty in prenatally undernourished female rats. Increased leptin resistance in the kisspeptin system might be involved in these alterations.
Assuntos
Hipotálamo/embriologia , Hipotálamo/metabolismo , Desnutrição/embriologia , Desnutrição/metabolismo , Proteínas/metabolismo , Animais , Feminino , Hipotálamo/crescimento & desenvolvimento , Kisspeptinas , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE AND DESIGN: Free radicals/reactive oxygen species (ROS) are related to inflammation, aging, and cancer. However, living systems have essential antioxidant mechanisms by which these harmful radicals can be scavenged, i.e., free radical-scavenging activity (FRSA). We measured the circadian rhythm of such activities by detecting salivary FRSA in healthy adults, and also examined how salivary FRSA is affected by physical and mental activities, which included (1) ingestion of beverage, (2) exercise, (3) comfortable/uncomfortable stimulation, and (4) smoking. METHODS: FRSA was determined by using the DPPH (1,1'-diphenyl-2-picrylhydrazyl) method. Statistical analysis for experimentally obtained median values was carried out using the Wilcoxon signed rank test. RESULTS: In circadian rhythm, FRSA was increased by food ingestion and relaxation. As to the individual activities, green tea and coffee ingestion increased FRSA, whereas swimming (P < 0.05) and dance lessons (P < 0.01) decreased it. Watching an amusing video program (P < 0.001) or stimulation by a pleasant aroma (P < 0.01) increased FRSA. In contrast, an unpleasant odor had no effect on FRSA. FRSA decreased immediately after smoking (P < 0.05), but increased thereafter (P < 0.01). CONCLUSION: Salivary FRSA was affected not only by physical activities, but also by mental activities. It may be a parameter for reflecting the health status of individuals.
Assuntos
Atividades Cotidianas , Antioxidantes/fisiologia , Sequestradores de Radicais Livres/farmacologia , Processos Mentais , Saliva/fisiologia , Adolescente , Adulto , Compostos de Bifenilo , Criança , Pré-Escolar , Ritmo Circadiano/fisiologia , Café , Dança/fisiologia , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/fisiologia , Exercício Físico/fisiologia , Feminino , Hemiterpenos , Humanos , Hidrazinas , Riso/fisiologia , Lavandula , Masculino , Pessoa de Meia-Idade , Óleos Voláteis , Ácidos Pentanoicos , Picratos , Óleos de Plantas , Relaxamento/fisiologia , Olfato/fisiologia , Fumar/fisiopatologia , Natação/fisiologia , Chá , Adulto JovemRESUMO
High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Esquema de Medicação , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The prognostic value of serum ferritin level in patients with peripheral T-cell lymphoma (PTCL) remains unknown. METHODS: We retrospectively analyzed clinical data from 78 consecutive patients with newly diagnosed PTCL that were treated with anthracycline-containing regimens between 1998 and 2011. RESULTS: The patients consisted of 50 males and 28 females with a median age of 64 years (range, 16-83 years). The subtypes of PTCL were 39 PTCL, not otherwise specified and 39 angioimmunoblastic T-cell lymphoma (AITL). The median observation period for the surviving patients was 50 months. The overall survival (OS) was poorer in patients with serum ferritin level above the upper normal limit (n = 28), compared with patients with serum ferritin level within normal range (n = 50; 4-year OS: 23% vs. 72%; P < 0.001). In the multivariate analysis, poor performance status (P = 0.006) and elevated serum ferritin level (P = 0.018) were independent risk factors for poor OS. CONCLUSION: Serum ferritin level is a useful prognostic marker for PTCL.
Assuntos
Ferritinas/sangue , Linfoma de Células T Periférico/sangue , Linfoma de Células T Periférico/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.
Assuntos
Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Histona Desmetilases/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores Etários , Variações do Número de Cópias de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/genética , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Contagem de Leucócitos , Masculino , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Transdução de Sinais , Sequenciamento do ExomaRESUMO
In vitro studies have demonstrated that prolonged N-methyl-D-aspartate receptor (NMDAR) blockade triggers a homeostatic up-regulation of NMDARs at synapses. Such upregulation can also be seen within 30 min in vivo in adult rats, implicating trafficking of reserve pools of NMDARs. Here, we evaluated the involvement of filamentous actin (F-actin), the major cytoskeletal component in spines, in this rapid in vivo homeostatic response, using biotinylated phalloidin as its probe. We also immuno-labeled spines for drebrin A, an F-actin-binding protein found at excitatory synapses and with a proposed role of modulating F-actin's cross-linking with one another and interactions with NMDARs. Quantitative 2-D analysis of ultrastructural images revealed that NMDAR blockade increased filamentous actin labeling per spine by 62.5% (P<0.005). The proportion of dendritic spines immuno-labeled for drebrin A also increased significantly, from 67.5% to 85% following NMDAR blockade (P<0.001), especially among larger spines. The frequency distributions of spine widths and postsynaptic density lengths were not affected by the D-(+)-2-amino-5-phosphonopentanoic acid (D-APV) treatment. However, the average postsynaptic density length was reduced by 25 nm among the fewer, drebrin A immuno-negative spines, indicating that drebrin A confers stability to synapse size. We propose that, in a homeostatic in vivo response, increases of drebrin A and F-actin within spines can enhance NMDAR trafficking by reducing cytoskeletal rigidity within the spine cytoplasm without changing the overt morphology of axo-spinous synapses. Alternatively or in addition, the cytoskeletal redistribution within spine cytoplasm may be triggered by the D-APV-induced, homeostatic up-regulation of NMDAR.
Assuntos
Citoesqueleto de Actina/metabolismo , Córtex Cerebral/metabolismo , Espinhas Dendríticas/metabolismo , Neuropeptídeos/biossíntese , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Citoesqueleto de Actina/ultraestrutura , Fatores Etários , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/ultraestrutura , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/ultraestrutura , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/biossínteseRESUMO
To elucidate a possible link between the cytotoxicity and Ca(2+) mobilization by (meth)acrylates, we investigated the cell survival of and change in [Ca(2+)](i) in human salivary gland (HSG) cells (salivary gland carcinoma cell line) and human gingival fibroblasts (HGF) cells treated separately with 9 (meth)acrylate monomers used in dentistry. The cell survival was determined by the MTT method, and the [Ca(2+)](i) changes after the stimulation with the (meth)acrylate monomers were measured in floating indo-1/AM-loaded cells in Ca(2+)-free medium. For both HSG and HGF cells, the cytotoxicity of the monomers was approximately proportional to their hydrophobicity (logP). No increase in [Ca(2+)](i) was found with hydrophilic monomers, even with 10mm stimulation. [Ca(2+)](i) elevation by hydrophobic monomers occurred in a dose- and hydrophobic-dependent manner. The [Ca(2+)](i) change in HSG cells appeared as twin peaks, i.e., an initial sharp peak followed by a delayed broad one; whereas with the HGF cells only a single broad peak was seen, possibly dependent on their membrane quality. Pretreatment with n-butanol or methylmethacrylate enhanced the butylmethacrylate-induced [Ca(2+)](i) elevation, suggesting the [Ca(2+)](i) elevation by (meth)acrylate may be related to monomer hydrophobicity and cell type. The causal link between the cytotoxicity and [Ca(2+)](i) mobilization of monomers is discussed.
Assuntos
Cálcio/metabolismo , Materiais Dentários/toxicidade , Gengiva/efeitos dos fármacos , Metacrilatos/toxicidade , Glândulas Salivares/efeitos dos fármacos , Butanóis/farmacologia , Cálcio/análise , Carcinoma , Cátions Bivalentes/metabolismo , Sobrevivência Celular , Células Cultivadas , Criança , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Gengiva/citologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias das Glândulas Salivares , Glândulas Salivares/citologia , Glândulas Salivares/metabolismo , Células Tumorais CultivadasRESUMO
Amphiphilic compounds such as long-chain acyl carnitine accumulate in ischemic myocardium and potentially contribute to the myocardial damage, and the role of carnitine in protecting the heart against ischemic damage is interesting. It has been reported that palmitoylcarnitine causes alterations in the membrane molecular dynamics, so this study was designed to investigate whether L-carnitine had a stabilizing effect of membrane fluidity using the spin-label technique. Human erythrocytes were spin-labeled with 5-doxylstearic acids, and membrane fluidity was quantified by measuring the change in the order parameter S. The administration of palmitoylcarnitine (100 microM) altered the membrane fluidity of erythrocytes and caused significant morphological changes. L-carnitine (2mM) decreased the alteration of the fluidity of erythrocytes incubated with palmitoylcarnitine (100 microM), and improved the morphological changes in erythrocytes. These results show that L-carnitine has a stabilizing effect of membrane fluidity as a result of interaction with the palmitoylcarnitine which has a detergent effect.
Assuntos
Carnitina/análogos & derivados , Carnitina/farmacologia , Membrana Eritrocítica/metabolismo , Fluidez de Membrana/efeitos dos fármacos , Palmitoilcarnitina/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/ultraestrutura , Humanos , Cinética , Microscopia Eletrônica de VarreduraRESUMO
To evaluate the efficacy of reduced-intensity stem-cell transplantation (RIST), we retrospectively compared outcomes of 207 consecutive Japanese patients aged between 50 and 59 years with hematologic malignancies who received RIST (n=70) and conventional stem-cell transplantation (CST) (n=137). CST recipients received total body irradiation (TBI)-based or busulfan/cyclophosphamide-based regimens. RIST regimens were purine analog-based (n=67), 2 Gy TBI-based (n=2), and others (n=1). Most CST recipients (129/137) received calcineurin inhibitors and methotrexate as graft-versus-host (GVHD) prophylaxis, while 32 RIST recipients received cyclosporin. In all, 23 CST and five RIST recipients died without disease progression within 100 days of transplant. Grade II to IV acute GVHD occurred in 56 CST and 38 RIST recipients. There was no significant difference in overall survival (OS) and progression-free survival between CST and RIST. On multivariate analysis on OS, five variables were significant: preparative regimens (CST vs RIST) (hazard ratio=1.92, 95% confidence interval, 1.25-2.97; P=0.003), performance status (2-4 vs 0-1) (2.50, 1.51-4.16; P<0.001), risk of underlying diseases (1.85, 1.21-2.83; P=0.004), acute GVHD (2.57, 1.72-3.84; P<0.001), and CML (0.38, 0.21-0.69; P=0.002). We should be careful in interpreting results of this small-sized retrospective study; however, reduced regimen-related toxicity might contribute to better survival in RIST. The low relapse rates following RIST suggest a strong antitumor activity through allogeneic immunity.
Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/terapia , Recidiva , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/imunologia , Transplante Homólogo/métodosRESUMO
Calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, CMA-676, has recently been introduced to clinics as a promising drug to treat patients with acute myeloid leukemia (AML) in relapse. However, the mechanism of action of CMA-676 has not been well elucidated. The cytotoxic effect of CMA-676 on HL60, NOMO-1, NB4, NKM-1, K562, Daudi, and the multidrug-resistant sublines, NOMO-1/ADR and NB4/MDR, was investigated by cell cycle distribution and morphology. These studies were done by a video-microscopic system, DNA fragmentation, dye exclusion and 3H-thymidine uptake after analysis of CD33, CD34, P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein and lung-related protein on these cells. A dose-dependent, selective cytotoxic effect of CMA-676 was observed in cell lines that expressed CD33, and was dependent on the amount of CD33 and the proliferative speed of the cells. Sensitive cells were temporally arrested at the G2/M phase before undergoing morphological changes. CMA-676 is not effective on P-gp-expressing multidrug-resistant sublines compared with parental cell lines. MDR modifiers, MS209 and PSC833, restored the cytotoxic effect of CMA-676 in P-gp-expressing sublines. CMA-676 is a promising agent in the treatment of patients with AML that expresses CD33. The combined use of CMA-676 and MDR modifiers may increase the selective cytotoxic effect in multidrug-resistant AML.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aminoglicosídeos , Antibacterianos/imunologia , Anticorpos Monoclonais/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Imunotoxinas/imunologia , Leucemia/imunologia , Anticorpos Monoclonais Humanizados , Ciclo Celular , Divisão Celular , Fragmentação do DNA , Citometria de Fluxo , Gemtuzumab , Humanos , Leucemia/metabolismo , Leucemia/patologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Células Tumorais CultivadasRESUMO
In a 27-year-old female with Turner syndrome mosaic, Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) occurred only in the monosomic cells (45, Xc). Extensive cytogenetic studies, including triple-color fluorescence in situ hybridization (FISH), revealed that Ph-positive monosomic cells (45, Xc), Ph-negative monosomic cells and normal diploid cells (46, XX) were present in her bone marrow at diagnosis. After successful interferon therapy, the non-leukemia cells expanded and reconstituted normal hematopoiesis resulting in complete cytogenetic response, following the selective suppression of the monosomic Ph-positive leukemia clone. The ratio of Xc to XX cells in bone marrow cells was significantly increased to that in skin fibroblasts. Moreover, the ratio of Ph-positive cells to Ph-negative cells was found to be significantly different between karyotyping and FISH. Studies of this quite unique case not only confirmed the clonality of CML, effectiveness of interferon-alpha and X chromosome imbalance among different tissues, but also demonstrated a discrepant increase of the BCR/ABL-positive clone in CML. The latter supports the hypothesis that reduced programmed cell death may be the primary mechanism responsible for the expansion of the leukemia clone in CML. Our study verifies the importance of extensive analysis of a neoplastic disease in patients with a constitutional chromosomal abnormality.
Assuntos
Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Monossomia/genética , Mosaicismo/genética , Síndrome de Turner/genética , Adulto , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Contagem de Células/efeitos dos fármacos , Distribuição de Qui-Quadrado , Células Clonais/efeitos dos fármacos , Células Clonais/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas de Fusão bcr-abl/genética , Humanos , Hibridização in Situ Fluorescente , Interferon-alfa/farmacologia , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/complicações , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/terapia , Monossomia/patologia , Mosaicismo/patologia , Indução de Remissão , Pele , Síndrome de Turner/complicações , Síndrome de Turner/patologia , Cromossomo X/genéticaRESUMO
Arsenic trioxide (As2O3) has recently been shown to induce complete remission in acute promyelocytic leukemia (APL). As2O3 reportedly has dose-dependent dual effects on APL cells, triggering apoptosis at relatively high concentrations and inducing differentiation at lower concentrations. However, its effect is still controversial for other AML cells and hematological neoplasms. We studied the in vitro effect of As2O3 on lymphoid lineage cells: lymphoma cell lines, NOL-3, Raji and Daudi, a myeloma cell line, NOP-1, normal peripheral blood lymphocytes (PBL), non-Hodgkin's lymphoma (NHL) cells and chronic lymphocytic leukemia (CLL) cells, and compared it with the effect on APL cell line, NB4, as well as other myeloid cell lines, HL-60 and NKM-1. As2O3 at a concentration of 1 micromol/l markedly inhibited both proliferation and viability of NB4, NOP-1, NOL-3 and NKM-1 cells, but it reduced only viability in normal PBL, CLL cells and NHL cells. As2O3 induced apoptosis and down-regulated bcl-2 expression in NB4, NOP-1 and NKM-1 cells. On the other hand, in HL-60, Raji and Daudi cells, 1 micromol/l As2O3 inhibited only the proliferation weakly, and neither induced apoptosis nor down-regulated bcl-2 expression, but arrested only cell cycle at G1 phase. As2O3 at a low concentration of 0.1 micromol/l had no effect on proliferation and viability of these cells except for NB4. These results showed that As2O3 exerted variable and definite effects on lymphoid cells and indicated that As2O3 might be clinically useful in lymphoid neoplasms such as malignant lymphoma and CLL.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Interfase/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B , Linfoma não Hodgkin , Óxidos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Trióxido de Arsênio , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA , DNA de Neoplasias , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Interleukin-12 (IL-12) has potent antitumor activities. We examined whether IL-12 enhanced the cytotoxicity of peripheral blood mononuclear cells (PBMNC) and decreased leukemia cells in 30 patients with leukemia or myelodysplastic syndromes (MDS): 12 acute myeloid leukemia (AML) (five in complete remission (CR) and seven in non-CR); six chronic myeloid leukemia (CML); and 12 MDS (three refractory anemia (RA), eight RA with excess of blasts and one chronic myelomonocytic leukemia). PBMNC from patients and five healthy volunteers were cultured at 5 x 10(5)/ml parallel with or without 100 units/ml of IL-12 for 3 days. Cytotoxicity of PBMNC against K562 cells was assessed by flow cytometry. To quantify the amount of leukemia cells, WT1 mRNA was measured by competitive reverse transcription polymerase chain reaction (RT-PCR), since WT1 mRNA is considered as a marker of minimal residual disease (MRD) in leukemia or MDS. The cytotoxicity of non-IL-12-treated PBMNC of 30 patients was 13.4+/-9.3% at the effector to target (E:T) ratio of 20:1, and significantly lower than that of normal subjects (25.7+/-8.4%). The cytotoxicity increased to 30.6+/-17.9% in the IL-12-treated PBMNC. WT1 mRNA in PBMNC of five healthy volunteers was less than 10(3) copies/microg of total RNA. Following the 3-day IL-12 treatment, mean WT1 mRNA of PBMNC was reduced from 10(4.8) to 10(4.2) copies/microg of total RNA in six CML patients, from 10(5.4) to 10(4.8) copies/microg in 12 MDS patients and from 10(5.0) to 10(4.2) copies/microg in five AML patients in CR, but not reduced in five of seven AML in non-CR. These results showed that IL-12 significantly enhanced PBMNC cytotoxicity and decreased the quantity of leukemia cells in PBMNC of most patients with MDS, CML and AML in CR. IL-12 might be of considerable benefit in the elimination of MRD in patients with hematological malignancies.
Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Interleucina-2/farmacologia , Leucemia/genética , Leucócitos Mononucleares/efeitos dos fármacos , Síndromes Mielodisplásicas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Feminino , Humanos , Interleucina-2/uso terapêutico , Células K562 , Leucemia/sangue , Leucemia/patologia , Leucócitos Mononucleares/fisiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas WT1RESUMO
Recent studies have shown that arsenic trioxide (As(2)O(3)) can induce complete remission in patients with acute promyelocytic leukemia (APL). We tested the efficacy and safety of As(2)O(3) for the treatment of patients with APL who had relapsed from or become refractory to all-trans retinoic acid (ATRA) and conventional chemotherapy in a prospective study. As(2)O(3) at a dose of 0.15 mg/kg was administered until the date of bone marrow remission to a maximum of 60 days. In patients who achieved complete remission (CR), one additional course of As(2)O(3) was administered using the same dose for 25 days. Of 14 patients, 11 (78%) achieved CR. Six of 10 patients who achieved CR showed disappearance of PML-RARalpha transcript by RT-PCR assay. The duration of As(2)O(3)-induced CR ranged from 4 to 22 months (median, 8 months) at a median follow-up of 17 months. Adverse events included 13 electrocardiogram abnormalities (13 QTc prolongation, eight ventricular premature contraction, four nonsustained ventricular tachycardia and two paroxysmal supraventricular tachycardia), seven nausea and vomiting, four pruritus, three peripheral neuropathy, three fluid retention and one APL differentiation syndrome. Four patients received antiarrhythmic agents. Hyperleukocytosis developed in five patients and in three cytotoxic drugs were necessary. Other adverse events were relatively mild. As(2)O(3) treatment is effective and relatively safe in relapsed or refectory patients with APL. Cardiac toxicities in patients with QTc prolongation should be carefully monitored.
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Adulto , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Trióxido de Arsênio , Arsenicais/efeitos adversos , Diferenciação Celular , Monitoramento de Medicamentos , Eletrocardiografia , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Óxidos/efeitos adversos , Estudos Prospectivos , Indução de Remissão , Tretinoína/uso terapêuticoRESUMO
Eugenol (compound in , 4-allyl-2-methyoxyphenol) and isoeugenol (compound in , 4-propenyl-2-methoxyphenol), both used as a flavor agent in cosmetic and food products, have both prooxidant and antioxidant activities. Their adverse effects such as allergic and inflammatory reaction may be due to their prooxidant activity. To clarify the mechanisms of their cytotoxicity and the factors affecting their antioxidant/prooxidant activities, we investigated the cytotoxicity, ROS production, and cellular glutathione (GSH) levels induced by eugenol and isoeugenol in a human submandibular cell line. The cytotoxicity (MTT method) of eugenol was 1 order of magnitude lower than that of isoeugenol (CC50: eugenol, 0.395 mM; isoeugenol, 0.0523 mM); and ROS production (CDF staining) was induced significantly by isoeugenol, but not by eugenol. Under treatment with H2O2 (100 microM) plus horseradish peroxidase (1 microg/ml) for 30 min or with visible light irradiation for 5 min, eugenol caused biphasic ROS production characterized by enhanced at lower eugenol concentrations (5-10 microM) and decreased at higher concentrations (500 microM). In contrast, isoeugenol enhanced ROS production over a wide range of concentrations (5-500 microM). Isoeugenol at 1000 microM significantly reduced GSH levels compared with eugenol at the same concentration. The high cytotoxicity of isoeugenol may be attributed to its induction of high ROS production and low GSH levels, possibly as a result of benzyl radical formation. In contrast, the cytotoxicity of eugenol is likely to be mediated by ROS-independent mechanisms, possibly involving phenoxyl radicals and/or eugenol quinone methide.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Eugenol/análogos & derivados , Eugenol/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/toxicidade , Linhagem Celular Tumoral , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Oxirredução , Estresse OxidativoRESUMO
When discussing treatment options for patients with acute leukemia, it is important to acknowledge the impact of allogeneic hematopoietic cell transplantation (allo-HCT) or chemotherapy on quality of life (QOL). We performed a cross-sectional questionnaire study that administered SF-36, FACT-Leukemia and EuroQOL5D to 524 acute leukemia survivors, to compare patient-reported QOL between chemotherapy and allo-HCT, and to elucidate predictors of QOL. Patients who received chemotherapy alone had a better physical QOL than those who received allo-HCT. On the other hand, the allo-HCT group reported a better mental QOL. In the comparison of QOL in the allo-HCT patients according to the presence of GVHD at survey, patients who had GVHD symptoms experienced statistically and clinically significantly worse QOL than those who did not. In the allo-HCT patients without GVHD, the physical QOL was comparable to that in the chemotherapy patients, and they experienced significantly better mental and general QOL than the chemotherapy patients. GVHD and immunosuppressive drugs at survey were strongly associated with worse QOL after allo-HCT. In the chemotherapy group, a shorter time between treatment completion and survey was significantly associated with worse QOL. Further evaluation of QOL by a longitudinal assessment with quantitative and qualitative analyses are warranted.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Qualidade de Vida , Autorrelato , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Humanos , Pessoa de Meia-IdadeRESUMO
Allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with relapsed follicular lymphoma (FL). Prospective studies of reduced-intensity conditioning (RIC) have revealed that chemosensitivity at allo-SCT is the most reliable predictor of outcome; however, limited data are available for progressive/refractory disease. We report here a retrospective analysis of RIC allo-SCT for patients with FL. The purpose of this study was to elucidate the role of allo-SCT for patients with relapsed/refractory FL. We analyzed 46 patients-11 (24%) transplanted in CR, 6 (13%) transplanted in PR and 29 (63%) with progressive/refractory disease. The estimated 5-year overall survival rate was 71.6% (95% confidence interval (CI), 51.5-84.5%). According to the disease status at transplantation, the 5-year survival rate was 80.7% (95% CI, 37.7-95.4%) in the patients with CR or PR and 66.1% (95% CI, 41.5-82.3%) in those with progressive/refractory disease (P=0.29). There were no differences in relapse/progression and non-relapse mortality between the patients with chemosensitive disease and progressive/refractory disease. Allo-SCT may be a valuable treatment option, even for patients with progressive/refractory FL.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Folicular/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto , Idoso , Feminino , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: The management of pregnant women with acute leukemia is usually challenging. We collected data concerning pregnant women with acute leukemia in the Kanagawa area in Japan. METHODS: A questionnaire was sent to 24 institutions in the Kanagawa area. RESULTS: Data were obtained for 11 patients, median age of 31 years (range, 20-36). Eight patients had acute myeloid leukemia and three had acute lymphoblastic leukemia. Six patients were diagnosed in the first trimester of pregnancy, one in the second trimester, and four in the third trimester. Five of six patients diagnosed in the first trimester had abortions before chemotherapy, and one had an elective abortion after receiving chemotherapy. All patients diagnosed in the second or third trimester delivered live infants. Of the six patients diagnosed in the first trimester, two died of recurrent leukemia, and four remained in remission. Of the five patients diagnosed in the second or third trimester, four achieved complete remission and remained in remission. One patient died of sepsis 4 days after cesarean section. CONCLUSIONS: Careful surveillance and monitoring of the fetus and close co-operation among hematologists, gynecologists, and pediatricians are essential to successfully treat pregnant women with acute leukemia.