RESUMO
In women, ovarian hormone loss associated with menopause has been related to cognitive decline. Hormone therapy (HT) may ameliorate some of these changes. Understanding the cognitive impact of female steroids, including estrogens, progestogens, and androgens, is key to discovering treatments that promote brain health in women. The preclinical literature has presented elegant and methodical experiments allowing a better understanding of parameters driving the cognitive consequences of ovarian hormone loss and HT. Animal models have been a valuable tool in this regard, and will be vital to future discoveries. Here, we provide an update on the literature evaluating the impact of female steroid hormones on cognition, and the putative mechanisms mediating these effects. We focus on preclinical work that was done with an eye toward clinical realities. Parameters that govern the cognitive efficacy of HT, from what we know thus far, include but are not limited to: type, dose, duration, and route of HT, age at HT initiation, timing of HT relative to ovarian hormone loss, memory type examined, menopause history, and hormone receptor status. Researchers have identified intricate relationships between some of these factors by studying their individual effects on cognition. As of late, there is increased focus on studying interactions between these variables as well as multiple hormone types when administered concomitantly. This is key to translating preclinical data to the clinic, wherein women typically have concurrent exposure to endogenous ovarian hormones as well as exogenous combination HTs, which include both estrogens and progestins. Gains in understanding the parameters of HT effects on cognition provide exciting novel avenues that can inform clinical treatments, eventually expanding the window of opportunity to optimally enhance cognition and brain health in aging women. This article is part of a Special Issue entitled Hormone Therapy.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Terapia de Reposição de Estrogênios/métodos , Aprendizagem em Labirinto/efeitos dos fármacos , Esteroides/uso terapêutico , Envelhecimento/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , RatosAssuntos
Medula Óssea/patologia , Diferenciação Celular , Células-Tronco Mesenquimais/patologia , Mieloma Múltiplo/patologia , Osteogênese , Receptores Notch/antagonistas & inibidores , Animais , Medula Óssea/metabolismo , Ensaio de Unidades Formadoras de Colônias , Feto/patologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/metabolismo , Receptores Notch/genética , Transdução de Sinais , Células Tumorais CultivadasAssuntos
Proliferação de Células , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Receptores Notch/metabolismo , Sindecana-1/metabolismo , Animais , Western Blotting , Proteínas de Ligação ao Cálcio , Diferenciação Celular , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Camundongos , Mieloma Múltiplo/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Notch/genética , Sindecana-1/genética , Células Tumorais CultivadasRESUMO
Multiple myeloma (MM) is a B-cell malignancy, which often remains incurable because of the development of drug resistance governed by the bone marrow (BM) microenvironment. Novel treatment strategies are therefore urgently needed. In this study, we evaluated the anti-MM activity of JNJ-26481585, a novel 'second-generation' pyrimidyl-hydroxamic acid-based histone deacetylase inhibitor, using the syngeneic murine 5TMM model of MM. In vitro, JNJ-26481585 induced caspase cascade activation and upregulation of p21, resulting in apoptosis and cell cycle arrest in the myeloma cells at low nanomolar concentrations. Similar results could be observed in BM endothelial cells using higher concentrations, indicating the selectivity of JNJ-26481585 toward cancer cells. In a prophylactic and therapeutic setting, treatment with JNJ-26481585 resulted in an almost complete reduction of the tumor load and a significant decrease in angiogenesis. 5T2MM-bearing mice also developed a MM-related bone disease, characterized by increased osteoclast number, development of osteolytic lesions and a reduction in cancellous bone. Treatment of these mice with JNJ-264815 significantly reduced the development of bone disease. These data suggest that JNJ-26481585 has a potent anti-MM activity that can overcome the stimulatory effect of the BM microenvironment in vivo making this drug a promising new anti-MM agent.
Assuntos
Modelos Animais de Doenças , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/etiologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Ciclo Celular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Osteólise/tratamento farmacológico , Osteólise/etiologiaRESUMO
Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC(50) of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 microg kg(-1) daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Modelos Animais de Doenças , Mieloma Múltiplo/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Western Blotting , Ciclo Celular , Replicação do DNA/efeitos dos fármacos , Depsipeptídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/patologia , Peptídeos Cíclicos , RatosRESUMO
The cell surface expression of CD9, a glycoprotein of the tetraspanin family influencing several processes including cell motility and metastasis, inversely correlates with progression in several solid tumors. In the present work, we studied the expression and role of CD9 in multiple myeloma (MM) biology using the 5T33MM mouse model. The 5T33MMvitro cells were found to be CD9 negative. Injection of these cells in mice caused upregulation of CD9 expression, while reculturing them resulted in downregulation of CD9. Coculturing of CD9-negative 5T33MMvitro cells with BM endothelial cells (BMECs) resulted in a partial retrieval of CD9. Laser microdissection followed by real-time polymerase chain reaction and immunohistochemistry performed on bone sections of 5T33MMvivo diseased mice demonstrated strong local expression of CD9 on MM cells in contact with BMEC compared to MM cells further away. These findings were also confirmed by immunohistochemistry in MM patients. Neutralizing anti-CD9 antibodies inhibited transendothelial invasion of CD9-expressing human MM5.1 and murine 5T33MMvivo cells. In conclusion, we provide evidence that CD9 expression by the MM cells is upregulated in vivo by close interaction of the cells with BMEC and that CD9 is involved in transendothelial invasion, thus possibly mediating homing and/or spreading of the MM cells.
Assuntos
Antígenos CD/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Animais , Antígenos CD/genética , Biópsia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Comunicação Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Mieloma Múltiplo/fisiopatologia , Invasividade Neoplásica , Tetraspanina 29 , Regulação para CimaRESUMO
Multiple myeloma (MM) is an incurable B-cell cancer characterised by the monoclonal proliferation of tumour cells in the bone marrow (BM). It has been described that matrix metalloproteinases (MMPs) and especially MMP-9 is secreted by MM cells. In this study, we investigated the possibility to exploit MMP-9 activity to activate prodrugs and to target MM cells as a new tumour-specific therapy. Cleavage of the prodrug EV1-FITC by MMP-9 resulted in release of fluorescence which can be used as a measure of prodrug activation. The 5T33MM mouse model was used in this proof-of-principle study. The prodrug was activated in a higher amount by addition to MMP-9-producing 5T33MMvv cells, homogenates from tumour-bearing organs (BM, spleen) and isolated 5T33MM-diseased BM and spleen cells compared to non-MMP-9-producing 5T33MMvt cells and homogenates/cells from non-tumour-bearing organs/mice, as measured by fluorescence release. This fluorescence release could be inhibited by the MMP-2/MMP-9-specific inhibitor, CTT. Activation of the prodrug in the 5T33MM spleen and BM homogenates was confirmed by chromatography. EV1-fluorescein isothiocyanate injection into 5T33MM-diseased animals resulted in a higher fluorescence release by the isolated BM and spleen cells compared to injection into healthy animals. In conclusion, MMP-9 activity can be used to activate prodrugs that target MM.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Fluoresceínas/uso terapêutico , Metaloproteinase 9 da Matriz/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Biotransformação , Células da Medula Óssea/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fluoresceínas/síntese química , Fluoresceínas/metabolismo , Fluorescência , Metaloproteinase 9 da Matriz/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Mieloma Múltiplo/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
Increased microvessel density (MVD) has been observed in the bone marrow (BM) of patients with multiple myeloma (MM), acute lymphoblastic leukaemia, acute myeloid leukaemia, and myelodysplastic and myeloproliferative syndrome. The MVD is the net result of cumulative phases of angiogenesis and angio-regression and is as such not an indicator of the ongoing angiogenesis at the time of biopsy. There is, therefore, a need for additional methods that allow the estimation of ongoing angiogenesis. Double immunostainings for CD34 and Ki-67 can be used on paraffin-embedded tissue to determine the endothelial proliferation fraction. The BM endothelial cells, as a component of the BM stroma, have a close interaction with the malignant cells. In MM, for example, they are involved in the specific homing and are a source of paracrine growth factors. Targeting the BM microvessels will not only influence the nutrient and oxygen supply, but will in addition reduce the growth stimuli provided by the EC.
Assuntos
Medula Óssea/fisiopatologia , Endotélio Vascular/patologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/fisiopatologia , Transtornos Mieloproliferativos/patologia , Neovascularização Patológica , Inibidores da Angiogênese/uso terapêutico , Animais , Antígenos CD34/análise , Medula Óssea/irrigação sanguínea , Medula Óssea/imunologia , Medula Óssea/patologia , Divisão Celular , Hipóxia Celular , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Microcirculação , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/fisiopatologiaRESUMO
The migration of multiple myeloma (MM) cells from the circulation into the bone marrow (BM) implicates that they must have the capacity to cross the BM endothelium including the subendothelial basement membrane. In this study, human CD138+ MM cells were immunomagnetically isolated from BM samples of MM patients and their invasion through Matrigel, that is, a reconstituted basement membrane, was determined. We demonstrated that primary MM cells have the capacity to transmigrate through basement membrane and that this invasiveness was considerably increased when assessed on Matrigel filters coated with BM endothelial cells (EC) (4LHBMEC line) (transendothelial invasion). The isolated MM cells were shown by zymography to secrete matrix metalloproteinase (MMP)-9 and anti-MMP-9 antibodies inhibited transendothelial invasion, indicating that MMP-9 is involved in this process. BM EC were found to increase the MMP-9 secretion in MM cells, indicating that EC enhance MM cell invasion through stimulation of MMP-9 secretion. BM EC were found to produce hepatocyte growth factor (HGF), and this cytokine also stimulated MMP-9 secretion in MM cells, while anti-HGF antibodies significantly inhibited EC-stimulated MM cell invasion. In summary, our findings provide evidence that MM cell-BM EC interactions enhance the invasion of human MM cells through stimulation of MMP-9 secretion.
Assuntos
Células da Medula Óssea/fisiologia , Células Endoteliais/fisiologia , Fator de Crescimento de Hepatócito/fisiologia , Metaloproteinase 9 da Matriz/fisiologia , Mieloma Múltiplo/patologia , Células Cultivadas , Humanos , Mieloma Múltiplo/enzimologia , Invasividade Neoplásica , Regulação para CimaRESUMO
Insulin-like growth factor-1 (IGF-1) has been described as an important factor in proliferation, cell survival and migration of multiple myeloma (MM) cells. Angiogenesis correlates with development and prognosis of the MM disease. Vascular endothelial growth factor (VEGF) is one of the prominent factors involved in this process. The different functions of IGF-1 were investigated in the 5TMM mouse model with emphasis on proliferation, migration and VEGF secretion, and the signalling pathways involved. Western Blot analysis revealed that ERK1/2 and Akt (PKB) were activated after IGF-1 stimulation. The activation of ERK1/2 was reduced by the PI3K inhibitor Wortmannin, implying that the PI3K pathway is involved in its activation. Insulin-like growth factor-1 induced an increase in DNA synthesis in MM cells, which was mediated by a PI3K/Akt-MEK/ERK pathway. Insulin-like growth factor-1 enhanced F-actin assembly and this process was only PI3K mediated. Stimulation by IGF-1 of VEGF production was reduced by PD98059, indicating that only the MEK-ERK pathway is involved in IGF-1-stimulated VEGF production. In conclusion, IGF-1 mediates its multiple effects on MM cells through different signal transduction pathways. In the future, we can study the potential in vivo effects of IGF-1 inhibition on tumour growth and angiogenesis in MM.
Assuntos
Quimiotaxia/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mieloma Múltiplo/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Flavonoides/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Mieloma Múltiplo/metabolismo , Neovascularização Patológica/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0-5 post-BMT (IL-6 and IL-8, P<0.05) and days 6-10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0-5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2-4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Interleucina-6/sangue , Interleucina-8/sangue , Leucemia/terapia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Bacteriemia/sangue , Bacteriemia/etiologia , Bacteriemia/patologia , Proteína C-Reativa/análise , Síndrome de Vazamento Capilar/sangue , Síndrome de Vazamento Capilar/etiologia , Síndrome de Vazamento Capilar/patologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Hepatopatia Veno-Oclusiva/sangue , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/patologia , Humanos , Leucemia/sangue , Masculino , Defeitos do Tubo Neural/terapia , Pneumonia/sangue , Pneumonia/etiologia , Pneumonia/patologia , Fatores de Risco , Condicionamento Pré-Transplante/efeitos adversos , Transplante HomólogoRESUMO
The restricted bone marrow (BM) localisation of multiple myeloma (MM) cells most likely results from a specific homing influenced by chemotactic factors, combined with the proper signals for growth and survival provided by the BM microenvironment. In analogy to the migration and homing of normal lymphocytes, one can hypothesise that the BM homing of MM cells is mediated by a multistep process, involving the concerted action of adhesion molecules and chemokines. In this study, we report that primary MM cells and myeloma derived cell lines (Karpas, LP-1 and MM5.1) express the chemokine receptor CCR2. In addition, we found that the monocyte chemotactic proteins (MCPs) MCP-1, -2 and -3, three chemokines acting as prominent ligands for CCR2, are produced by stromal cells, cultured from normal and MM BM samples. Conditioned medium (CM) from BM stromal cells, as well as MCP-1, -2 and -3, act as chemoattractants for human MM cells. Moreover, a blocking antibody against CCR2, as well as a combination of neutralizing antibodies against MCP-1, -2 and -3, significantly reduced the migration of human MM cells to BM stromal cell CM. The results obtained in this study indicate the involvement of CCR2 and the MCPs in the BM homing of human MM cells.
Assuntos
Movimento Celular , Quimiocina CCL2/biossíntese , Citocinas , Regulação Neoplásica da Expressão Gênica , Proteínas Quimioatraentes de Monócitos/biossíntese , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Receptores de Quimiocinas/biossíntese , Medula Óssea/patologia , Adesão Celular , Quimiocina CCL7 , Quimiocina CCL8 , Humanos , Receptores CCR2 , Receptores de Quimiocinas/análise , Células Estromais/fisiologia , Células Tumorais CultivadasRESUMO
Multiple myeloma (MM) is a malignant B cell disorder characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM) and the presence of monoclonal immunoglobulin in serum and/or urine. Despite recent advances in the understanding of the pathophysiology of MM, the exact etiology of MM still remains unknown. MM cells are characterized by a profound degree of genetic instability with several chromosomal abnormalities. The survival and proliferation of MM cells are largely dependent on a supportive microenvironment. The development and progression of MM can be regard as a multistep process of molecular alterations resulting in uncontrolled growth and therapy resistance. Although considerable progress has been made in the therapy of MM, it still remains an uncurable disease with conventional treatment. Novel therapeutic modalities targeting the MM cell and the microenvironment such as inhibitors of angiogenesis (thalidomide and derivatives, arsenic trioxide) and inhibitors of transcription factor NF-kappa B (proteasome inhibitors) are currently being evaluated in clinical trials and hopefully will result in prolonged disease-free and overall survival.
Assuntos
Mieloma Múltiplo/terapia , Adjuvantes Imunológicos/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Citocinas/fisiologia , Humanos , Imunoterapia , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/imunologia , Plasmócitos/patologiaRESUMO
We present the case of an 80-year-old male with an history of multiple myeloma (MM) stage I with extramedullary plasmacytoma of the neck, diagnosed 18 months before and in complete remission after radiation therapy and melphalan-prednisone therapy. He was admitted with signs and symptoms characteristic for cavernous sinus syndrome, including diplopia, exophthalmia, ptosis and orbital pain. Magnetic resonance imaging showed a mass lesion in the cavernous sinus, consistent with relapsing extramedullary plasmacytoma. The patient received palliative radiation therapy and high dose dexamethasone, but treatment failed and the patient died. This case represents one of the few reports of extramedullary plasmacytoma of the cavernous sinus. The development of a clinical presentation of cavernous sinus syndrome in a patient with a history of MM or extramedullary plasmacytoma should raise the suspicion of a plasmacytic involvement of the cavernous sinus.
Assuntos
Seio Cavernoso , Plasmocitoma/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Humanos , Imageamento por Ressonância Magnética , Masculino , Plasmocitoma/terapia , Tomografia Computadorizada por Raios XRESUMO
We monitored levels of C-reactive protein (CRP) in 96 consecutive adult allogeneic BMT patients (age 15-50 years) transplanted in our unit. Major transplant-related complications (MTC) occurred in 32% of cases and included: hepatic veno-occlusive disease, pneumonitis, severe endothelial leakage syndrome and >II acute GVHD. Transplant-related mortality (TRM) before day 100 post-BMT was 13.5%. Variables included in a stepwise logistic regression model were: gender, age, disease category, donor type, T cell depletion, TBI, use of growth factors, bacteremia, mean CRP-levels >50 mg/l between days 0 and 5 (CRP day 0-5) and >100 mg/l between days 6 and 10 (CRP day 6-10) post-BMT. Only high CRP-levels (for MTC and TRM) (P < 0.001) and donor-type (for TRM) (P= 0.02) were independent risk factors. The estimated probability for MTC was 73% (CRP day 6-10 >100 mg/l) vs 17% (CRP day 6-10 <100 mg/l). Using the same cut-off levels, the probabilities for TRM were 36.5% vs 1% in the identical sibling donor situation and 88% vs 12.5% in other donor-type transplants. We conclude that the degree of systemic inflammation, as reflected by CRP-levels, during the first 5-10 days after BMT identifies patients at risk of MTC and TRM. Our data may be useful in selecting patients for clinical trials involving pre-emptive anti-inflammatory treatment.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/mortalidade , Proteína C-Reativa/metabolismo , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Doenças Hematológicas/complicações , Doenças Hematológicas/mortalidade , Doenças Hematológicas/terapia , Humanos , Incidência , Inflamação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Transplante HomólogoRESUMO
Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis.
Assuntos
Aorta/citologia , Comunicação Celular , Mieloma Múltiplo/patologia , Neovascularização Patológica/fisiopatologia , Animais , Aorta/patologia , Bioensaio , Modelos Animais de Doenças , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação , Mieloma Múltiplo/veterinária , FenótipoRESUMO
In this single-center study, a consecutive cohort of 59 adult patients transplanted with HLA-identical bone marrow and receiving graft-versus-host disease (GVHD) prophylaxis with either standard cyclosporine/methotrexate (n = 33) or partial T cell depletion (E-rosetting) (TCD, n = 26 were analyzed). Only patients with chronic myeloid leukemia in first chronic phase or acute leukemia/myelodysplasia in first or second remission were included. Except for age (median 28 vs 42 years), both groups were comparable in terms of diagnosis, conditioning regimen and growth factor support. TCD significantly reduced >grade II acute GVHD (0 vs 24%, P = 0.02), chronic GVHD (8.5 vs 45%, P = 0.007) and other major bone marrow transplant (BMT)-related complications (4 vs 36%, P = 0.005). TCD decreased overall transplant-related mortality (11.5 vs 36%, P = 0.04). In the TCD group faster neutrophil (13 vs 22 days, P = 0.02) and platelet recoveries (18 vs 26 days, P < 0.001) were noted. The relapse risk was higher after TCD (57.5 vs 21.5%, P = 0.04). Overall survival probability at 10 years was identical in both groups (54 vs 53.5%, P = 0.33). We found a relationship between the number of T cells in the graft and the occurrence of major complications (P < 0.001) and relapse (P = 0.03). This comparative analysis shows that graft-derived T cells have a major role in overall BMT-related toxicity and that partial TCD is an acceptable approach in terms of survival for patients between 40 and 50 years of age.
Assuntos
Transplante de Medula Óssea/métodos , Leucemia/terapia , Depleção Linfocítica , Linfócitos T/citologia , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/mortalidade , Estudos de Coortes , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Cinética , Leucemia/complicações , Leucemia/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Transplante Homólogo , Transplante IsogênicoRESUMO
Multiple myeloma is a B-cell malignancy characterized by the accumulation of plasma cells in the bone marrow and the development of osteolytic bone disease. The present study demonstrates that myeloma cells express the critical osteoclastogenic factor RANKL (the ligand for receptor activator of NF-kappa B). Injection of 5T2MM myeloma cells into C57BL/KaLwRij mice resulted in the development of bone disease characterized by a significant decrease in cancellous bone volume in the tibial and femoral metaphyses, an increase in osteoclast formation, and radiologic evidence of osteolytic bone lesions. Dual-energy x-ray absorptiometry demonstrated a decrease in bone mineral density (BMD) at each of these sites. Treatment of mice with established myeloma with recombinant osteoprotegerin (OPG) protein, the soluble decoy receptor for RANKL, prevented the development of lytic bone lesions. OPG treatment was associated with preservation of cancellous bone volume and inhibition of osteoclast formation. OPG also promoted an increase in femoral, tibial, and vertebral BMD. These data suggest that the RANKL/RANK/OPG system may play a critical role in the development of osteolytic bone disease in multiple myeloma and that targeting this system may have therapeutic potential.