RESUMO
In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Análise Citogenética , Dexametasona/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidrazinas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Oligopeptídeos/administração & dosagem , Prognóstico , Recidiva , Retratamento , Resultado do Tratamento , Triazóis/administração & dosagemRESUMO
Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood-brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain.
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Selenium (Se) is an essential micronutrient that exerts multiple and complex effects on human health. Se is essential for human well-being largely due to its potent antioxidant, anti-inflammatory, and antiviral properties. The physiological functions of Se are carried out by selenoproteins, in which Se is specifically incorporated as the amino acid, selenocysteine. Importantly, both beneficial and toxic effects of Se have been reported suggesting that the mode of action of Se is strictly chemical form and concentration dependent. Additionally, there is a relatively narrow window between Se deficiency and toxicity and growing evidence suggests that Se health effects depend greatly on the baseline level of this micronutrient. Thus, Se supplementation is not an easy task and requires an individualized approach. It is essential that we continue to explore and better characterize Se containing compounds and mechanisms of action, which could be crucial for disease prevention and treatment.
Assuntos
Antioxidantes/metabolismo , Micronutrientes/metabolismo , Selênio/metabolismo , Selenoproteínas/metabolismo , Humanos , Compostos de Selênio/metabolismo , Selenocisteína/metabolismoAssuntos
Atitude do Pessoal de Saúde , Tomada de Decisão Clínica , Conhecimentos, Atitudes e Prática em Saúde , Mieloma Múltiplo/patologia , Neoplasia Residual/psicologia , Médicos/psicologia , Padrões de Prática Médica , Exame de Medula Óssea/métodos , Progressão da Doença , Citometria de Fluxo , Pesquisas sobre Atenção à Saúde , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mieloma Múltiplo/psicologia , Mieloma Múltiplo/terapia , Neoplasia Residual/diagnóstico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sensibilidade e Especificidade , Inquéritos e Questionários , Fatores de TempoRESUMO
Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 ± 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression.
Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas/secundário , Condicionamento Físico Animal , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Metástase NeoplásicaRESUMO
VE-cadherin-mediated cell-cell junction weakening increases paracellular permeability in response to both angiogenic and inflammatory stimuli. Although Semaphorin 3A has emerged as one of the few known anti-angiogenic factors to exhibit pro-permeability activity, little is known about how it triggers vascular leakage. Here we report that Semaphorin 3A induced VE-cadherin serine phosphorylation and internalisation, cell-cell junction destabilisation, and loss of barrier integrity in brain endothelial cells. In addition, high-grade glioma-isolated tumour-initiating cells were found to secrete Semaphorin 3A, which promoted brain endothelial monolayer permeability. From a mechanistic standpoint, Semaphorin 3A impinged upon the basal activity of the serine phosphatase PP2A and disrupted PP2A interaction with VE-cadherin, leading to cell-cell junction disorganization and increased permeability. Accordingly, both pharmacological inhibition and siRNA-based knockdown of PP2A mimicked Semaphorin 3A effects on VE-cadherin. Hence, local Semaphorin 3A production impacts on the PP2A/VE-cadherin equilibrium and contributes to elevated vascular permeability.
Assuntos
Permeabilidade da Membrana Celular , Células Endoteliais/enzimologia , Células Endoteliais/patologia , Proteína Fosfatase 2/metabolismo , Semaforina-3A/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Ativação Enzimática , Glioma/enzimologia , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/metabolismo , Proteína Fosfatase 2/antagonistas & inibidores , Quinases da Família src/metabolismoRESUMO
DEP-1/CD148 is a receptor-like protein tyrosine phosphatase with antiproliferative and tumor-suppressive functions. Interestingly, it also positively regulates Src family kinases in hematopoietic and endothelial cells, where we showed it promotes VE-cadherin-associated Src activation and endothelial cell survival upon VEGF stimulation. However, the molecular mechanism involved and its biologic functions in endothelial cells remain ill-defined. We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. Accordingly, RNA interference (RNAi)-mediated knockdown of DEP-1 or expression of DEP-1 Y1311F/Y1320F impairs Src-dependent biologic responses mediated by VEGF including permeability, invasion, and branching capillary formation. In addition, our work further reveals that above a threshold expression level, DEP-1 can also dephosphorylate Src Y418 and attenuate downstream signaling and biologic responses, consistent with the quiescent behavior of confluent endothelial cells that express the highest levels of endogenous DEP-1. Collectively, our findings identify the VEGF-dependent phosphorylation of DEP-1 as a novel mechanism controlling Src activation, and show this is essential for the proper regulation of permeability and the promotion of the angiogenic response.
Assuntos
Capilares/metabolismo , Permeabilidade da Membrana Celular , Endotélio Vascular/citologia , Neovascularização Patológica , Tirosina/metabolismo , Quinases da Família src/metabolismo , Antígenos CD/metabolismo , Western Blotting , Caderinas/metabolismo , Adesão Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Cortactina/metabolismo , Endotélio Vascular/metabolismo , Imunofluorescência , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunoprecipitação , Mutação/genética , Invasividade Neoplásica , Fosforilação , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: The endothelial specific cell-cell adhesion molecule, VE-cadherin, modulates barrier function and vascular homeostasis. In this context, we have previously characterized that VEGF (vascular endothelial growth factor) leads to VE-cadherin phosphorylation, ß-arrestin2 recruitment and VE-cadherin internalization in mouse endothelial cells. However, exactly how this VE-cadherin/ß-arrestin complex contributes to VEGF-mediated permeability in human endothelial cells remains unclear. In this study, we investigated in-depth the VE-cadherin/ß-arrestin interactions in human endothelial cells exposed to VEGF. FINDINGS: First, we demonstrated that VEGF induces VE-cadherin internalization in a clathrin-dependent manner in human umbilical vein endothelial cells (HUVEC). In addition to the classical components of endocytic vesicles, ß-arrestin1 was recruited and bound to phosphorylated VE-cadherin. Molecular mapping of this interaction uncovered that the C-terminus tail of ß-arrestin1, that comprises amino acids 375 to 418, was sufficient to directly interact with the phosphorylated form of VE-cadherin. Interestingly, the expression of the C-terminus tail of ß-arrestin1 induced loss of surface exposed-VE-cadherin, promoted monolayer disorganization and enhanced permeability. Finally, this effect relied on decreased VE-cadherin expression at the transcriptional level, through inhibition of its promoter activity. CONCLUSIONS: Altogether, our results demonstrate that ß-arrestin1 might play multiple functions collectively contributing to endothelial barrier properties. Indeed, in addition to a direct implication in VE-cadherin endocytosis, ß-arrestin1 could also control VE-cadherin transcription and expression. Ultimately, understanding the molecular mechanisms involved in VE-cadherin function might provide therapeutic tools for many human diseases where the vascular barrier is compromised.
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Metastases are the leading cause of cancer mortality and their development may be affected by diet. The aim of this study was to compare the effects of dietary supplementation with different selenium (Se) compounds on the dynamics of brain metastasis development in a novel mouse model. Mice were fed experimental diets enriched (1 mg/kg) with sodium selenite (Se-S), seleno-1-methionine (Se-Meth), a yeast-derived organic form of selenium (Se-Yeast), or a control diet (Se < 0.05 mg/kg) for 20 wk. At the end of the feeding period, animals were injected with luciferase-tagged K1735 (K1735-Luc) melanoma cells into the brain vasculature. The development of brain metastatic tumors was monitored for 2 wk following injection. Mice bearing brain metastatic tumors and fed Se-Yeast- or Se-S-enriched diets displayed a higher survival rate compared with other experimental and control groups. Importantly, Se-Yeast supplementation decreased the growth of brain metastatic tumors as determined by the measurement of the intensity of the bioluminescent signal emitted by K1735-Luc cells upon reaction with luciferin. Different chemical forms of Se have distinct effects on the development of brain metastases. Organic Se in the form of Se-Yeast may be a valuable agent in suppression of brain metastatic disease.
Assuntos
Neoplasias Encefálicas/dietoterapia , Neoplasias Encefálicas/patologia , Selênio/farmacologia , Fermento Seco/farmacologia , Animais , Antineoplásicos/farmacologia , Peso Corporal/efeitos dos fármacos , Neoplasias Encefálicas/mortalidade , Movimento Celular/efeitos dos fármacos , Suplementos Nutricionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/dietoterapia , Neoplasias Experimentais/patologiaRESUMO
The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing models are urgently needed. Zebrafish are a powerful vertebrate model in preclinical cancer research. Here, we describe a zebrafish neuroblastoma yolk sac model to evaluate efficacy and toxicity of histone deacetylase (HDAC) inhibitor treatments. Larvae were engrafted with fluorescently labeled, genetically diverse, established cell lines and short-term cultures of patient-derived primary cells. Engrafted tumors progressed locally and disseminated remotely in an intact environment. Combination treatments involving the standard chemotherapy doxorubicin and HDAC inhibitors substantially reduced tumor volume, induced tumor cell death, and inhibited tumor cell dissemination to the tail region. Hence, this model allows for fast, cost-efficient, and reliable in vivo evaluation of toxicity and response of the primary and metastatic tumor sites to drug combinations.
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Despite several recommendations for standardization of multiparameter flow cytometry (MFC) the number, specificity and combinations of reagents used by diagnostic laboratories for the diagnosis and classification of acute leukemias (AL) are still very diverse. Furthermore, the current diagnostic interpretation of flow cytometry readouts is influenced arbitrarily by individual experience and knowledge. We determined the potential value of a minimal four-color combination panel of 13 monoclonal antibodies (mAbs) with a CD45/sideward light scatter-gating strategy for a standardized MFC immunophenotyping of the clinically most relevant subgroups of AL. Bone marrow samples from 155 patients with acute myeloid leukemia (AML, n=79), B-cell precursor acute lymphoblastic leukemia (BCP-ALL, n=29), T-cell precursor acute lymphoblastic leukemia (T-ALL, n=12) and normal bone marrow donors (NBMD, n=35) were analyzed. A knowledge-based learning algorithm was generated by comparing the results of the minimal panel with the actual diagnosis, using discriminative function analysis. Correct classification of the test sample according to lineage, that is, BCP-ALL, T-ALL, AML and differentiation of NBMD was achieved in 97.2% of all cases with only six of the originally applied 13 mAbs of the panel. This provides evidence that discriminant function analysis can be utilized as a decision support system for interpretation of flow cytometry readouts.
Assuntos
Diagnóstico por Computador/métodos , Citometria de Fluxo/métodos , Leucemia/diagnóstico , Doença Aguda , Algoritmos , Anticorpos Monoclonais , Medula Óssea/patologia , Linhagem da Célula , Cor , Diagnóstico por Computador/instrumentação , Diagnóstico por Computador/normas , Citometria de Fluxo/normas , Humanos , Imunofenotipagem , Padrões de ReferênciaRESUMO
The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3-6 µM PCI-34051 or 10 µM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05 µM (ALK-amplified) to 0.8 µM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n = 88) and the German Neuroblastoma Trial cohort (n = 649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma.
Assuntos
Quinase do Linfoma Anaplásico/genética , Antineoplásicos/farmacologia , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Proteínas Repressoras/antagonistas & inibidores , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Crizotinibe/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células Tumorais Cultivadas , Peixe-ZebraRESUMO
Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here we show that both static 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D-grown cells are substantially different from those of 3D-grown cells and tumor tissue. Autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models more closely mimic tumor (patho-)physiology, including the upregulation of tumor relevant pathways, such as autophagy.
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Autofagia/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.
Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Metástase Neoplásica/tratamento farmacológico , Selênio/farmacologia , Molécula de Adesão de Leucócito Ativado/genética , Molécula de Adesão de Leucócito Ativado/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Lewis/patologia , Suplementos Nutricionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Selênio/administração & dosagem , Selênio/uso terapêutico , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoAssuntos
Dexametasona/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Neoplasia Residual/diagnóstico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Neoplasia Residual/sangue , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Transplante AutólogoRESUMO
To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Cladribina/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Selenium-containing compounds and selenized yeast have anticancer properties. In order to address possible mechanisms involved in these effects, selenoglycoproteins (SGPs) were extracted from selenium-enriched yeast at pH 4.0 and 6.5 (the fractions are called SGP40 and SGP65, respectively), followed by evaluation of their impact on the interactions of lung and breast tumor cells with human brain microvascular endothelial cells (HBMECs). Extracted SGPs, especially SGP40, significantly inhibited adhesion of tumor cells to HBMECs and their transendothelial migration. Because the active components of SGPs are unknown, small selenium-containing compounds [leucyl-valyl-selenomethionyl-arginine (LVSe-MR) and methylselenoadenosine (M-Se-A)], which are normally present in selenized yeast, were introduced as additional treatment groups. Treatment of HBMECs with SGP40, LVSe-MR and M-Se-A induced changes in gene signatures, which suggested a central involvement of nuclear factor (NF)-κB-dependent pathway. These observations were confirmed in the subsequent analysis of NF-κB DNA binding activity, quantitative measurements of the expression of selected genes and proteins, and tumor cell adhesion assay with a specific NF-κB inhibitor as the additional treatment factor. These findings indicate that specific organic selenium-containing compounds have the ability to inhibit tumor cell adhesion to brain endothelial cells via down-regulation of NF-κB. SGPs appear to be more effective than small selenium-containing compounds, suggesting the role of not only selenium but also the glycoprotein component in the observed protective impact.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Glicoproteínas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Saccharomyces cerevisiae/farmacologia , Selenoproteínas/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Endotélio Vascular/citologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicoproteínas/biossíntese , Glicoproteínas/isolamento & purificação , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Microvasos/citologia , Microvasos/efeitos dos fármacos , NF-kappa B/agonistas , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Compostos Organosselênicos/isolamento & purificação , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/farmacologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/biossíntese , Proteínas de Saccharomyces cerevisiae/isolamento & purificação , Selênio/metabolismo , Selenometionina/análogos & derivados , Selenometionina/isolamento & purificação , Selenometionina/metabolismo , Selenometionina/farmacologia , Selenoproteínas/biossíntese , Selenoproteínas/isolamento & purificação , Migração Transendotelial e Transepitelial/efeitos dos fármacosRESUMO
Autologous peripheral blood stem cell transplantation (APBSCT) is used similarly to autologous bone marrow transplantation (ABMT) to reconstitute bone marrow following myeloablative therapy in patients with proliferative diseases of the blood. Eight patients with recurrent and refractory lymphoma (3 HD, 4 NHL) and multiple myeloma aged 17-55 were included into the study. Peripheral blood stem cells following their prior mobilisation with cyclophosphamide 4-7 g/m2 and/or G-CFS or Dexa-BEAM + G-CSF were collected by subsequent leukaphereses on Fenwal CS3000. Nucleated cells were separated by sedimentation, cryopreserved in a programmed freezer and then stored at-196 degrees C. Bone marrow has been additionally collected in one patient. Conditioning treatment prior to transplantation consisted of BCNU, etoposide and cyclophosphamide (CBV) in lymphomas and melphalan in multiple myeloma. Collected material with mean cellularity 5.52 x 10(8)/kg and mean CD34+ contents 6.27 x 10(6)/kg was reinfused by central line. G-CSF was given in 5 patients to hasten the bone marrow recovery. All patients fully recovered and left hospital on average 35.5 days following transplantation. No signs of relapse were seen throughout the observation period (mean 349.5 days). Neutrophils > 0.5 G/1 were obtained on day + 20, > 1.0 G/1 on day 30, platelets > 50 G/1 on day 29, > 100 G/1 on day 53, reticulocytes > 0.015 on day 30, erythrocytes transfusions were needed up to day 39. Presented outcomes together with other reports indicate, that APBSCT is a highly efficient way to rescue repeatedly relapsing patients with proliferative diseases of the lymphatic systems, even those presenting with changes in the bone marrow (neoplasmatic infiltrate, hypoplasia or fibrosis).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma/terapia , Adolescente , Adulto , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Hematopoese , Humanos , Leucaférese , Masculino , Pessoa de Meia-Idade , Recidiva , Transplante AutólogoRESUMO
We evaluated the feasibility of allogeneic transplantation of CliniMACS-selected peripheral CD34+ cells from siblings (four patients: AML-M4, M2, CLL, MDS); nonoptimal related donors (two patients: AML-M4, CML); and unrelated donors (two patients: CML, ALL, both without engraftment after preceding URDBMT). All patients had high-risk of aGVHD and/or graft failure due to multiple transplantation risk factors. Conditioning treatment was myeloablative (n=7) or nonmyeloablative (n=1). Immunosuppression consisted of CsA (n=8), Mtx (n=5), ATG (n=4). Selected CD34+ cells were transplanted (average 3.91 x 10(6)/kg, range 1.29 to 7.27 x 10(6)/kg) together with 0.01 to 0.5 x 10(7) CD3+ cells/kg to assure proper engraftment. The remaining CD34-negative fraction was cryopreserved for further CD3+ cell add-back. Average recovery and purity of CD34+ cells following CliniMACS selection were 74% and 97%. No severe complications were observed in the first 100 days. Regeneration times were satisfactory in seven of eight patients (87.5%) with ANO > 0.5 g/L and Plt > 50 g/L reached on average on days +26 and +32 (range 15 to 29 and 15 to 67), respectively. In three patients (37.5%) T-lymphocytes were added-back one to three times (due to low numbers of initially transfused CD3+ cells in two patients, in one patient with PRCA caused by ABO incompatibility). One to four additional transplantations of nonselected peripheral cells were performed on days +28 to +270 in consequence of infections (CMV-two patients; parvovirus-one patient), poor regeneration and residual disease (one patient) and prolonged transfusion dependency (one patient). Severe aGVHD grade III or IV developed in three patients (37.5%) following the nonselected cells transplantation. Finally, five patients (62.5%) are alive and in remission (median follow-up 815 days). We conclude that allogeneic transplantation of selected peripheral CD34+ cells (CliniMACS) with controlled add-back of CD3+ cells is an effective, well, tolerated procedure in high-risk patients.