Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Eur J Gynaecol Oncol ; 37(2): 199-203, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27172745

RESUMO

PURPOSE OF INVESTIGATION: A retrospective study to evaluate six cycles of cisplatin 40 mg/m2 on day 1 and ifosfamide 1,200 mg/m2 daily on days 1 to 4 with Mesna every four weeks as first line treatment for 29 patients with a diagnosis of uterine carcinosarcoma. MATERIALS AND METHODS: A total of 23 of 29 patients received high dose rate intracavitary vaginal cuff brachytherapy (VCBT) with two fractions of seven Gy each. Median age was 65 years (range 40-82); 13 (44.8%) had Stage I disease, three (10.3%) had Stage II, eight (27.6%) had Stage III, and five (17.2%) patients had Stage IV disease. RESULTS: Most common toxicities were anemia grade 1 (35%)/grade 2 (45%), and neutropenia grade 3 (17%)/grade 4 (6.9%). Eleven dose modifications, four treatment discontinuations, and one patient withdrawal occurred. At a median follow up of 45 months (range 9 to 144), Progression free survival (PFS) was 20% and overall survival (OS) was 40% for Stage IV, PFS 75% and OS 62.5% for Stage III, compared to a PFS 75% and OS 72.2% for Stages I-II. Median OS for the entire group was 12.43 years (95% CI 3.69 to inf); for Stage I-III 12.4 years (6.1 to inf), and for Stage IV 15.6 months (95% CI 9.4 to inf). CONCLUSIONS: Cisplatin and ifosfamide chemotherapy with VCBT was well tolerated and has promising activity in uterine carcinosarcoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Carcinossarcoma/terapia , Neoplasias Uterinas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Carcinossarcoma/patologia , Quimiorradioterapia , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Ifosfamida/administração & dosagem , Mesna/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Substâncias Protetoras/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Uterinas/patologia
6.
Br J Cancer ; 111(9): 1750-6, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25268372

RESUMO

BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 µM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 µM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Técnicas In Vitro , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Br J Cancer ; 109(2): 462-71, 2013 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-23807163

RESUMO

BACKGROUND: We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. METHODS: We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear-cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours. RESULTS: Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-γ secretion) in SCGB2A1-specific CTLs. CONCLUSION: SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Mamoglobina B/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Mamoglobina B/genética , Análise em Microsséries , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Transcriptoma , Estudos de Validação como Assunto
8.
Oncogene ; 32(1): 39-49, 2013 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-22349827

RESUMO

Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that epithelial-ovarian cancer stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and mesenchymal-epithelial transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected intraperitoneally in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to 'home' to the ovaries and establish tumors. Most interestingly, we found that TWIST-1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST-1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells.


Assuntos
Diferenciação Celular , Metástase Neoplásica , Neoplasias Epiteliais e Glandulares/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Proteólise , Células Tumorais Cultivadas
9.
Br J Cancer ; 106(9): 1543-50, 2012 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-22531721

RESUMO

BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias do Colo do Útero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos CD55/química , Antígenos CD55/genética , Antígenos CD59/química , Antígenos CD59/genética , Ativação do Complemento , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Citotoxicidade Imunológica , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Trastuzumab , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia
10.
Br J Cancer ; 105(8): 1176-82, 2011 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-21915118

RESUMO

BACKGROUND: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. METHODS: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. RESULTS: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). CONCLUSION: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Genes erbB-2 , Neoplasias Uterinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Citotoxicidade Celular Dependente de Anticorpos , Meios de Cultivo Condicionados , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunoterapia , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Trastuzumab , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia
11.
Br J Cancer ; 103(6): 812-9, 2010 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-20700124

RESUMO

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF. METHODS: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h (51)Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50-100 IU ml(-1)). RESULTS: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing+/-s.d., 65.6+/-3.7%, range 57.5-77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC. CONCLUSION: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities.


Assuntos
Carcinoma Papilar/terapia , Fator VII/uso terapêutico , Imunoterapia , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Uterinas/terapia , Carcinoma Papilar/imunologia , Carcinoma Papilar/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Células Matadoras Naturais/imunologia , Reação em Cadeia da Polimerase , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/patologia
12.
Br J Cancer ; 102(1): 134-43, 2010 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-19920829

RESUMO

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.


Assuntos
Adenocarcinoma Papilar/patologia , Anticorpos Monoclonais/farmacologia , Neoplasias Uterinas/patologia , Idoso , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proteínas do Sistema Complemento/imunologia , Citotoxicidade Imunológica , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Imunoglobulina G/imunologia , Técnicas In Vitro , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Transdução de Sinais/efeitos dos fármacos , Trastuzumab
13.
Br J Cancer ; 101(2): 335-41, 2009 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-19536090

RESUMO

BACKGROUND: Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients. METHODS: SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied. RESULTS: SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT-PCR=162 vs 2.21; P=0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (mug ml(-1)) had a median (95% CIs) of 6.0 (4.0-8.9) in normal healthy females and 6.0 (4.2-8.1) in patients with benign disease (P=0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2-56.2), significantly higher than those in the healthy group (P=0.0005) and benign group (P=0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P=0.0024). CONCLUSION: SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Papilar/sangue , Cistadenocarcinoma Seroso/sangue , Proteína Amiloide A Sérica/biossíntese , Neoplasias Uterinas/sangue , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Amiloide A Sérica/genética , Células Tumorais Cultivadas , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
14.
Oncogene ; 27(34): 4712-23, 2008 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-18408758

RESUMO

Cancer progression is an abnormal form of tissue repair characterized by chronic inflammation. IkappaB kinase-beta (IKKbeta) required for nuclear factor-kappaB (NF-kappaB) activation plays a critical role in this process. Using EOC cells isolated from malignant ovarian cancer ascites and solid tumors, we identified IKKbeta as a major factor promoting a functional TLR-MyD88-NF-kappaB pathway that confers to EOC cell the capacity to constitutively secrete proinflammatory/protumor cytokines and therefore promoting tumor progression and chemoresistance. Furthermore, we describe for the first time the identification of the microRNA hsa-miR-199a as a regulator of IKKbeta expression. Our study describes the property of ovarian cancer cells to enhance the inflammatory microenvironment as a result of the expression of an active IKKbeta pathway. Identification of these markers in patients' tumor samples may facilitate the adequate selection of treatment and open new venues for the development of effective therapy for chemoresistant ovarian cancers.


Assuntos
Quinase I-kappa B/genética , MicroRNAs/fisiologia , NF-kappa B/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Sequência de Bases , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico , Transfecção , Células Tumorais Cultivadas
15.
Oncogene ; 27(2): 225-33, 2008 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-18176604

RESUMO

Cancer could be deemed as an abnormal and uncontrolled tissue repair process. Therefore, it would not be surprising that factors that function in the tissue repair process, such as cytokines, chemokines, growth factors and Toll-like receptor (TLR) ligands, as well as growth signals for compensatory proliferation, would also be key factors in regulating and enhancing cancer progression. The TLR pathways, which play a critical role in tissue repair, are also key regulators in cancer progression as well as chemoresistance. TLRs serve as cell surface sensors that can initiate pathways leading to proliferation and chemoresistance; as well as mediators that are able to regulate the infiltrating immune cells to provide further support for cancer progression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Receptores Toll-Like/genética , Receptores Toll-Like/fisiologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/fisiologia , Feminino , Humanos , Inflamação/complicações , MicroRNAs/uso terapêutico , Modelos Biológicos , Fator 88 de Diferenciação Mieloide/fisiologia , NF-kappa B/fisiologia , Neoplasias/etiologia , Neoplasias/patologia , Neoplasias/terapia , Infiltração de Neutrófilos/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Transdução de Sinais/genética , Receptor 4 Toll-Like/fisiologia , Receptores Toll-Like/metabolismo
16.
Int J Gynecol Cancer ; 18(1): 22-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17451459

RESUMO

The objective of this study was to evaluate the treatment and outcome in patients with ovarian carcinosarcoma. The Tumor Board Registry was reviewed for patients with ovarian carcinosarcoma treated at our institution from June 1993 to December 2004. The medical records were retrospectively analyzed with emphasis on cytoreduction, cytotoxic regimens, progression-free interval, and survival. Twenty-two patients were identified. All but two presented with advanced stage disease. The median survival for the entire cohort was 38 months. Median survival was 46 months for 18 optimally debulked (<1 cm) patients and 27 months for four suboptimally debulked (>1 cm) patients. Six patients were treated with optimal cytoreduction and adjuvant cisplatin (40 mg/m(2)x 1 day) and ifosfamide (1200 mg/m(2)/day x 4 days) every 28 days. Median progression-free interval in the cisplatin and ifosfamide group was 13 months, and median survival was 51 months. The combination of carboplatin (AUC 5) and taxol (175 mg/m(2)) every 21 days was administered to four patients as first-line chemotherapy following optimal cytoreduction. In the carboplatin and taxol group, median progression-free interval was 6 months and median survival was 38 months. The difference in survival between the cisplatin and ifosfamide group and the carboplatin and taxol group was not statistically significant (P= 0.48). In conclusion, patients with ovarian carcinosarcoma usually present with advanced stage disease. Treatment consists of optimal cytoreduction and chemotherapy. The most effective cytotoxic regimen remains to be determined. First-line cisplatin and ifosfamide or carboplatin and taxol can achieve survival rates observed in epithelial ovarian cancer.


Assuntos
Carcinossarcoma/terapia , Neoplasias Ovarianas/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/patologia , Carcinossarcoma/cirurgia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Ifosfamida/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...