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1.
Clin Cancer Res ; 11(18): 6722-9, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16166453

RESUMO

PURPOSE: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy. EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (gammaH2AX). RESULTS: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy x 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks. CONCLUSION: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/efeitos da radiação , Neoplasias do Sistema Nervoso Central/patologia , Terapia Combinada , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , DNA de Neoplasias/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Etoposídeo/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/radioterapia , Razoxano/administração & dosagem , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Células Tumorais Cultivadas
2.
APMIS ; 111(2): 300-8, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12716386

RESUMO

PURPOSE: Langerhans cell histiocytosis (LCH) is a disease with a variable clinical manifestation, being localised (SS) or disseminated (MS). The etiology and pathogenesis of LCH is unknown. It is a proliferative disorder of monoclonal origin, but not necessarily neoplastic. In our study we evaluated histopathological parameters and proliferative activity in LCH. MATERIALS AND METHODS: Infiltrates from 43 patients with LCH were investigated (nSS=32, nMS=11). We evaluated different histopathological parameters semiquantitatively, demonstrating proliferation using immunohistochemistry for Ki-67. RESULTS: Overall, the histopathological picture of LCH was heterogeneous. The degree of eosinophilia and presence of necroses was significantly higher in SS-infiltrates compared to MS-infiltrates. Mitotic figures were detected in more than half the infiltrates. The Langerhans origin was verified by CD1a. Ki-67 was highly expressed in all but one infiltrate. CONCLUSIONS: The presence of necrosis and the degree of eosinophilia are related to SS-disease in our study. Ki-67 expression and the presence of mitotic figures indicate that local proliferation contributes to the accumulation of Langerhans cells. Supported by the histopathological appearance of the lesions and a level of Ki-67 expression lower than that of neoplastic tissue, we suggest that LCH is a reactive condition, possibly induced by immunostimulation caused by unknown agents.


Assuntos
Histiocitose de Células de Langerhans/patologia , Antígeno Ki-67/análise , Biomarcadores Tumorais/análise , Divisão Celular , Criança , Eosinófilos/patologia , Humanos , Linfócitos/patologia , Mitose , Necrose , Plasmócitos/patologia
3.
J Pediatr Hematol Oncol ; 27(6): 301-6, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15956881

RESUMO

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in various organs. The etiology of LCH remains enigmatic. Fas/APO-1/CD95 belongs to the "death receptor" family of apoptosis regulators and has been implicated in the downregulation of immune responses. The authors examined the expression of three proteins that are engaged in the Fas signaling cascade-FADD/Fas-associated death domain-containing protein, FLICE/FADD-like interleukin-1beta-converting enzyme (both pro-apoptotic), and FLIP/FLICE-inhibitory protein (anti-apoptotic)-in lesions from LCH patients. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 43 children with LCH. The infiltrates were scored according to the amount of positive pathologic Langerhans cells (pLCs). In all investigated specimens, the majority of the pLCs expressed FADD, active FLICE, and FLIP. The clinical outcome of the disease could not be correlated to the expression of the investigated proteins. This study shows a high expression of the apoptosis-related proteins FADD, active FLICE, and FLIP in pLCs. The authors previously showed that pLCs express Fas and Fas ligand. Taken together, these findings suggest that the Fas signaling pathway may be involved in the pathogenesis of LCH.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Caspases/metabolismo , Histiocitose de Células de Langerhans/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Caspase 8 , Criança , Ativação Enzimática , Proteína de Domínio de Morte Associada a Fas , Humanos , Imuno-Histoquímica/métodos , Tonsila Palatina/citologia , Tonsila Palatina/patologia
4.
J Pediatr Hematol Oncol ; 24(9): 733-6, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12468914

RESUMO

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare pediatric and adult disease causing skin rashes, osteolytic bone lesions, tumorous growth in various organs, and in some patients, organ dysfunction. The cause of the disease is obscure, and it is not yet understood why some patients develop single-system lesions only without relapse, whereas others develop fatal multiorgan disease. The expression of p53 tumor suppressor gene product detected immunohistochemically can be used as a guideline to alterations in DNA repair control and apoptosis. The authors have chosen to analyze p53 expression in biopsies from children with LCH and correlate it with clinical manifestation and outcome in a broad range of organs. PATIENTS AND METHODS: The study was performed on 50 specimens from 32 children (19 boys and 13 girls), median age 3 1/4 years, range 5 months to 12 1/3 years with a definite diagnosis of LCH based on CD1a positivity. The slides were stained with p53 antibody and semiquantitatively evaluated using a grading system from 1 to 5 as an estimate for 0% to 20%, 20% to 40%, 40% to 60%, 60% to 80%, and 80% to 100% p53-positive for pathologic Langerhans cells (pLC), respectively. RESULTS: The p53 protein was expressed in various degrees in pLC in all lesions. The degree of p53 expression could not be correlated to either clinical manifestation or outcome. CONCLUSIONS: An increased expression of p53 in pLC indicates an altered DNA repair control with or without abnormal control of apoptosis.


Assuntos
Genes p53 , Histiocitose de Células de Langerhans/patologia , Proteína Supressora de Tumor p53/genética , Biópsia , Criança , Pré-Escolar , Feminino , Seguimentos , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
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