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1.
Br J Cancer ; 112(8): 1405-10, 2015 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-25867274

RESUMEN

BACKGROUND: The aim of this study was to examine whether EndoPredict (EP), a novel genomic expression test, is effective in predicting local recurrence (LR)-free survival (LRFS) following surgery for breast cancer in postmenopausal women. In addition, we examined whether EP may help tailor local therapy in these patients. METHODS: From January 1996 to June 2004, 3714 postmenopausal patients were randomly assigned to either tamoxifen or tamoxifen followed by anastrozole within the prospective ABCSG 8 trial. Using assay scores from EP, we classified breast tumour blocks as either low or high risk for recurrence. RESULTS: Data were gathered from 1324 patients. The median follow-up was 72.3 months and the cumulative incidence of LR was 2.6% (0.4% per year). The risk of LR over a 10-year period among patients with high-risk lesions (n=683) was significantly higher (LRFS=91%) when compared with patients with low-risk lesions (n=641) (10-year LRFS=97.5%) (HR: 1.31 (1.16-1.48) P<0.005). The groups that received breast conservation surgery (BCT) and mastectomy (MX) had similar LR rates (P=0.879). Radiotherapy (RT) after BCT significantly improved LRFS in the cohorts predicted by EP to be low-risk for LR (received RT: n=436, 10-year LRFS 99.8%; did not receive RT: n=63, 10-year LRFS 83.6%, P<0.005). CONCLUSIONS: EndoPredict is an effective prognostic tool for predicting LRFS. Among postmenopausal, low-risk patients, EP does not appear to be useful for tailoring local therapy.


Asunto(s)
Neoplasias de la Mama/genética , Recurrencia Local de Neoplasia/genética , ARN Neoplásico/análisis , Juego de Reactivos para Diagnóstico , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Posmenopausia , Estudios Prospectivos , Factores de Riesgo
2.
Br J Cancer ; 109(12): 2959-64, 2013 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-24157828

RESUMEN

BACKGROUND: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. METHODS: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis). RESULTS: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. CONCLUSION: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/biosíntesis , Anastrozol , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Diferenciación Celular/fisiología , Procesos de Crecimiento Celular/fisiología , Ensayos Clínicos Fase III como Asunto , Femenino , Perfilación de la Expresión Génica , Humanos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Nitrilos/administración & dosificación , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Estudios Retrospectivos , Transducción de Señal , Tamoxifeno/administración & dosificación , Tamoxifeno/uso terapéutico , Resultado del Tratamiento , Triazoles/administración & dosificación
3.
Ann Oncol ; 24(9): 2316-24, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23661292

RESUMEN

BACKGROUND: Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015). CONCLUSIONS: MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Mucina-1/metabolismo , Terapia Neoadyuvante , Biomarcadores de Tumor/genética , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Docetaxel , Doxorrubicina/uso terapéutico , Femenino , Expresión Génica , Humanos , Persona de Mediana Edad , Mucina-1/genética , ARN Mensajero/biosíntesis , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Sobrevida , Taxoides/uso terapéutico , Resultado del Tratamiento
4.
Ann Oncol ; 24(3): 640-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23035151

RESUMEN

BACKGROUND: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. PATIENTS AND METHODS: We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis. RESULTS: After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. CONCLUSION: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/diagnóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Anastrozol , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Nitrilos/administración & dosificación , Guías de Práctica Clínica como Asunto , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Tamoxifeno/administración & dosificación , Resultado del Tratamiento , Triazoles/administración & dosificación
5.
Ann Oncol ; 24(3): 632-9, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23131391

RESUMEN

BACKGROUND: Hormone and human epidermal growth factor receptor 2 (HER2) receptors are the most important breast cancer biomarkers, and additional objective and quantitative test methods such as messenger RNA (mRNA)-based quantitative analysis are urgently needed. In this study, we investigated the clinical validity of RT-PCR-based evaluation of estrogen receptor (ESR1) and HER2 mRNA expression. PATIENTS AND METHODS: A total of 1050 core biopsies from two retrospective (GeparTrio, GeparQuattro) and one prospective (PREDICT) neoadjuvant studies were evaluated by quantitative RT-PCR for ESR1 and HER2. RESULTS: ESR1 mRNA was significantly predictive for reduced response to neoadjuvant chemotherapy in univariate and multivariate analysis in all three cohorts. The complete pathologically documented response (pathological complete response, pCR) rate for ESR1+/HER2- tumors was 7.3%, 8.0% and 8.6%; for ESR1-/HER2- tumors it was 34.4%, 33.7% and 37.3% in GeparTrio, GeparQuattro and PREDICT, respectively (P < 0.001 in each cohort). In the Kaplan-Meier analysis in GeparTrio patients with ESR1+/HER2- tumors had the best prognosis, compared with ESR1-/HER2- and ESR1-/HER2+ tumors [disease-free survival (DFS): P < 0.0005, overall survival (OS): P < 0.0005]. CONCLUSIONS: Our results suggest that mRNA levels of ESR1 and HER2 predict response to neoadjuvant chemotherapy and are significantly associated with long-term outcome. As an additional option to standard immunohistochemistry and gene-array-based analysis, quantitative RT-PCR analysis might be useful for determination of the receptor status in breast cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Receptor alfa de Estrógeno/genética , Receptor ErbB-2/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/mortalidad , Receptor alfa de Estrógeno/metabolismo , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Análisis Multivariante , Terapia Neoadyuvante , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del Tratamiento
6.
Br J Cancer ; 107(11): 1892-900, 2012 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-23079573

RESUMEN

BACKGROUND: Biomarkers predictive of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) of breast cancer are urgently needed. METHODS: Using a training/validation approach for detection of predictive biomarkers in HER2-negative breast cancer, pre-therapeutic core biopsies from four independent cohorts were investigated: Gene array data were analysed in fresh frozen samples of two cohorts (n=86 and n=55). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in formalin-fixed, paraffin-embedded (FFPE) samples from two neoadjuvant phase III trials (GeparTrio, n=212, and GeparQuattro, n=383). RESULTS: A strong predictive capacity of thymosin beta 15 (TMSB15A) gene expression was evident in both fresh frozen cohorts (P<0.0001; P<0.0042). In the GeparTrio FFPE training cohort, a significant linear correlation between TMSB15A expression and pCR was apparent in triple-negative breast cancer (TNBC) (n=61, P=0.040). A cutoff point was then defined that divided TNBC into a low and a high expression group (pCR rate 16.0% vs 47.2%). Both linear correlation of TMSB15A mRNA levels (P=0.017) and the pre-defined cutoff point were validated in 134 TNBC from GeparQuattro (pCR rate 36.8% vs 17.0%, P=0.020). No significant predictive capacity was observed in luminal carcinomas from GeparTrio and GeparQuattro. CONCLUSION: In TNBC, TMSB15A gene expression analysis might help to select patients with a high chance for pCR after NACT.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Timosina/genética , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ensayos Clínicos Fase III como Asunto , Receptor alfa de Estrógeno/análisis , Femenino , Perfilación de la Expresión Génica , Humanos , Modelos Logísticos , ARN Mensajero/análisis , Receptor ErbB-2/análisis , Receptores de Progesterona/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
7.
Ann Oncol ; 23(6): 1422-7, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22056852

RESUMEN

BACKGROUND: The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. METHODS: Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. RESULTS: High UBE2C mRNA expression was associated with poor DFS (Wald's P = 0.003) and OS (Wald's P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). CONCLUSIONS: High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/metabolismo , ARN Mensajero/genética , Enzimas Ubiquitina-Conjugadoras/genética , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Metotrexato/administración & dosificación , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Transcripción Genética , Carga Tumoral , Enzimas Ubiquitina-Conjugadoras/metabolismo , Adulto Joven
8.
Breast Cancer Res Treat ; 126(1): 109-17, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21190079

RESUMEN

Human epidermal growth factor receptor 2 (HER2) testing is an essential part of pathological assessment in breast cancer patients, as HER2 provides not only prognostic but also predictive information on response to targeted therapy. So far, HER2 test accuracy of immunohistochemistry/in situ-hybridization techniques is still under debate, and more reliable and robust technologies are needed. To address this issue and to evaluate the predictive value of HER2 on chemotherapy, we investigated a cohort of 278 patients from the GeparTrio trial, a prospective neoadjuvant anthracycline/taxane-based multicenter study. In the GeparTrio trial, patients were not treated with any anti-HER2 therapy, as this was not standard therapy at this time. The HER2 status was analyzed by three different approaches: local and central evaluation using immunohistochemistry combined with in situ-hybridization as well as evaluation of HER2 mRNA expression using kinetic RT-PCR from formalin-fixed, paraffin-embedded (FFPE) tissue samples using a predefined cutoff. HER2 overexpression/amplification was observed in 37.3% (91/244) and 17.9% (41/229) of the informative samples in the local and central evaluations, respectively. Positive HER2 mRNA levels were found in 19.8% (55/278). We observed a highly significant correlation between central HER2 expression and HER2 status measured by kinetic RT-PCR (r = 0.856, P < 0.0001) and an overall agreement of 95.6% (κ statistic, 0.862, CI 0.77-0.94). Further, central HER2 as well as HER2 mRNA expression were predictors for a pathological complete response after neoadjuvant anthracycline/taxane-based primary chemotherapy in a univariate binary logistic regression analysis (OR 3.29, P = 0.002; OR 2.65, P = 0.004). The predictive value could be confirmed for the central HER2 status by multivariate analysis (OR 3.04, P = 0.027). The locally assessed HER2 status was not predictive of response to chemotherapy. Our results suggest that standardized methods are preferable for evaluation of HER2 status. The kinetic RT-PCR from FFPE tissue might be an additional approach for assessment of this important prognostic and predictive parameter but has to be confirmed by other studies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , ARN Mensajero/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Capecitabina , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Técnicas para Inmunoenzimas , Terapia Neoadyuvante , Pronóstico , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Taxoides/administración & dosificación , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina
9.
Leukemia ; 21(3): 494-504, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17252012

RESUMEN

In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.


Asunto(s)
Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/química , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Crónica/patología , Proteínas de Neoplasias/análisis , Células Madre Neoplásicas/química , Antígenos CD34/análisis , Apoptosis/genética , Adhesión Celular/genética , Diferenciación Celular/genética , División Celular/genética , ADN Complementario/genética , ADN de Neoplasias/genética , Proteínas de Fusión bcr-abl/análisis , Proteínas de Fusión bcr-abl/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , ARN Mensajero/genética , ARN Neoplásico/genética , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/genética , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento/genética , Receptores de Leptina , Transducción de Señal/genética , Regulación hacia Arriba
10.
Cancer Gene Ther ; 14(4): 431-9, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17235352

RESUMEN

In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adeno-associated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62-82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3-14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vector-mediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.


Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Genes p53/genética , Terapia Genética , Neoplasias Pulmonares/terapia , Inhibidores de Proteasas/uso terapéutico , Pirazinas/uso terapéutico , Apoptosis , Bortezomib , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Terapia Combinada , Docetaxel , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Guanina/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed , Inhibidores de Proteasoma , Taxoides/uso terapéutico , Transfección , Células Tumorales Cultivadas
11.
Nucleic Acids Res ; 27(22): 4328-34, 1999 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-10536139

RESUMEN

Up to now, out of approximately 20 antisense oligodeoxyribonucleotides (as ODN) selected and tested against a given target gene, only one species shows substantial suppression of target gene expression. In part, this seems to be related to the general assumption that the structures of local target sequences or antisense nucleic acids are unfavorable for efficient annealing. Experimental approaches to find effective as ODN are extremely expensive when including a large number of antisense species and when considering their moderate success. Here, we make use of a systematic alignment of computer-predicted secondary structures of local sequence stretches of the target RNA and of semi-empirical rules to identify favorable local target sequences and, hence, to design more effective as ODN. The intercellular adhesion molecule 1 (ICAM-1) gene was chosen as a target because it had been shown earlier to be sensitive to antisense-mediated gene suppression. By applying the protocol described here, 10 ICAM-1-directed as ODN species were found that showed substantially improved inhibition of target gene expression in the endothelial cell line ECV304 when compared with the most effective published as ODN. Further, 17 out of 34 antisense species (50%) selected on the theoretical basis described here showed significant (>50%) inhibition of ICAM-1 expression in mammalian cells.


Asunto(s)
Expresión Génica/efectos de los fármacos , Marcación de Gen , Molécula 1 de Adhesión Intercelular/genética , Oligodesoxirribonucleótidos Antisentido/farmacología , Línea Celular Transformada , Interpretación Estadística de Datos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Modelos Químicos , Oligodesoxirribonucleótidos Antisentido/química , Probabilidad , Relación Estructura-Actividad
12.
J Mol Biol ; 259(4): 632-44, 1996 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-8683570

RESUMEN

Efficacy and sequence specificity are two major requirements in the use of antisense nucleic acids and ribozymes. For long-chain complementary RNA sequences (>30 nt), effects in living cells are correlated with the association rate of the complementary RNA in vitro, but not with the stability of the formed double strand. Thus, sequence selectivity of complementary RNA has to be defined as fast versus slow annealing with the appropriate target or non-target sequences, respectively. In this work, we performed a systematic kinetic analysis to evaluate the selectivity of bcr-abl-directed antisense RNA and hammerhead ribozymes with a length of the complementary sequences of between 20 and 80 bases. By kinetic in vitro selection, we identified oligomeric as well as long-chain complementary RNA that annealed at least tenfold faster with the bcr-abl sequence in comparison with either of the wild-type sequences bcr or abl, respectively. In the presence of selected oligodeoxynucleotide sequences and RNase H, the bcr-abl transcript was specifically hydrolysed out of a mixture containing abl and bcr sequences as well. Hammerhead ribozymes were designed such that binding with their target was facilitated either via helix I or helix III-forming antisense arms but not both. Further, cleavage and binding occurred on opposite sides of the bcr-abl fusion point. Target selectivity was found for a ribozyme that annealed fast via abl sequences and cleaved within the bcr portion of bcr-abl RNA. Kinetic probing and calculations of the local folding potential indicate that the bcr-abl fusion point sequences are not easily accessible for complementary nucleic acids. This study supports the need for more detailed structural investigations of the bcr-abl fusion sequence and forms a more rational basis for the therapeutic use of nucleic acid inhibitors of the aberrant bcr-abl gene expression in Philadelphia chromosome-positive cells.


Asunto(s)
Genes abl , ARN sin Sentido/química , ARN sin Sentido/metabolismo , ARN Catalítico/metabolismo , ARN Complementario/metabolismo , Secuencia de Bases , Cartilla de ADN , Electroforesis en Gel de Poliacrilamida , Humanos , Cinética , Leucemia Mielógena Crónica BCR-ABL Positiva , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Hibridación de Ácido Nucleico , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/metabolismo , ARN Complementario/química , ARN Complementario/genética , ARN Bicatenario/química , ARN Bicatenario/genética , ARN Bicatenario/metabolismo , ARN Mensajero/metabolismo , Ribonucleasa H/metabolismo , Células Tumorales Cultivadas
13.
Bone Marrow Transplant ; 35(1): 33-6, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15531906

RESUMEN

Following induction therapy and 4 g/m(2) cyclophosphamide, a single dose of 12 mg polyethyleneglycol-conjugated G-CSF (pegfilgrastim; n=12) or daily doses of unconjugated G-CSF (8.5 mug/kg/day) (n=12) were administered to myeloma patients. Pegfilgrastim was associated with an earlier leukocyte recovery (12 vs 14 days) and peripheral blood CD34+ cell peak (12 vs 15 days). The peripheral blood CD34+ cell peak was lower in the pegfilgrastim group (78 vs 111/mul). Following high-dose melphalan (200 mg/m(2)) and autografting, leukocyte and platelet reconstitution was similar in both groups and stable blood counts were observed 100 days post transplant. In summary, a single dose of pegfilgrastim after chemotherapy is capable of mobilizing a sufficient number of CD34+ cells for successful autografting with early engraftment and sustained hematological reconstitution in patients with myeloma. These data provide the basis for randomized studies evaluating the optimal dose and time of pegfilgrastim as well as long-term outcome in larger cohorts of patients.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/análogos & derivados , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante de Células Madre/métodos , Células Madre/citología , Adulto , Antígenos CD34/biosíntesis , Plaquetas/citología , Ciclofosfamida/farmacología , Femenino , Filgrastim , Humanos , Cinética , Leucaféresis , Leucocitos/citología , Leucocitos/metabolismo , Masculino , Melfalán/farmacología , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Polietilenglicoles/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , Proteínas Recombinantes , Factores de Tiempo
14.
Exp Hematol ; 29(3): 380-90, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11274767

RESUMEN

OBJECTIVE: Mobilization of hematopoietic progenitor cells is achieved mainly by application of growth factors and, more recently, by blockade of adhesion. In this report, we describe the advantages of a combined treatment with granulocyte colony-stimulating factor (G-CSF) and anti-VLA4 (CD49d)/anti-CD44 as compared to treatment with the individual components. MATERIALS AND METHODS: Mobilization by intravenous injection of anti-CD44, anti-VLA4, or G-CSF was controlled in spleen and bone marrow with regard to frequencies of multipotential colony-forming unit (C-CFU), marrow repopulating ability, long-term reconstitution, recovery of myelopoiesis, and regain of immunocompetence. RESULTS: Mobilization by anti-CD44 had a strong effect on expansion of early progenitor cells in the bone marrow, while the recovery in the spleen was poor. In anti-CD49d-mobilized noncommitted and committed progenitors, progenitor expansion was less pronounced, but settlement in the spleen was quite efficient. Thus, anti-CD44 and anti-CD49d differently influenced mobilization. Accordingly, mobilization and recovery after transfer were improved by combining anti-CD44 with anti-CD49d treatment. Mobilization by G-CSF was most efficient with respect to recovery of progenitor cells in the spleen. However, when transferring G-CSF-mobilized cells, regain of immunocompetence was strongly delayed. This disadvantage could be overridden when progenitor cells were mobilized via blockade of adhesion and when expansion of these mobilized progenitor cells was supported by low-dose G-CSF only during the last 24 hours before transfer. CONCLUSION: Mobilization of pluripotent progenitor cells via antibody blockade of CD44 or CD49d or via G-CSF relies on distinct mechanisms. Therefore, the reconstitutive capacity of a transplant can be significantly improved by mobilization regimens combining antibody with low-dose G-CSF treatment.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Receptores de Hialuranos/inmunología , Integrinas/inmunología , Receptores Mensajeros de Linfocitos/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Trasplante de Médula Ósea , Adhesión Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Sinergismo Farmacológico , Supervivencia de Injerto , Células Madre Hematopoyéticas/citología , Inmunocompetencia , Integrina alfa4beta1 , Integrinas/antagonistas & inhibidores , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos , Quimera por Radiación , Receptores Mensajeros de Linfocitos/antagonistas & inhibidores , Bazo/citología
15.
Bone Marrow Transplant ; 28(1): 47-9, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11498743

RESUMEN

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated four patients with severe aGVHD refractory to steroids with infliximab, a chimeric human/mouse antiTNFalpha antibody. Patients (CML 2, MM 1, AML 1) developed grade III-IV GVHD at a median of 34 days (range 15-76) after myeloablative PBSCT (two), donor lymphocyte infusion for relapsed CML (one) or non-myeloablative PBSCT (one), respectively. All patients had severe intestinal involvement in addition to skin and/or liver disease and had received treatment with high-dose steroids (four) for a median of 11 days (range 5-17) in addition to CsA (four) and MMF (three). Infliximab (10 mg/kg) was given once a week until clinical improvement. In three of four patients a complete resolution of diarrhea and significant improvement of skin and liver disease were observed. Two patients received one, one patient two and one patient three infliximab infusions. At present two patients are alive >200 days after therapy, one with limited cGVHD. Two patients died, one of progressive malignant disease without GVHD and one of refractory GVHD. Infliximab is apparently an active drug for the treatment of aGVHD.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Aguda , Adulto , Animales , Antiinflamatorios/administración & dosificación , Femenino , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Infliximab , Masculino , Ratones , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/administración & dosificación , Terapia Recuperativa , Esteroides/uso terapéutico , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/inmunología
16.
Cancer Chemother Pharmacol ; 71(1): 245-55, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23096218

RESUMEN

PURPOSE: RACGAP1 is a Rac GTPase-activating protein involved in cell growth regulation, cell transformation and metastasis. The aim of the present study was to explore the prognostic and/or predictive significance of RACGAP1 mRNA expression on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients and compare it to that of Ki67 protein expression and to the Nottingham prognostic index (NPI). METHODS: A total of 595 high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel. RNA was extracted from 314 formalin-fixed paraffin-embedded primary tumor tissue samples followed by one-step quantitative RT-PCR for assessing RACGAP1 mRNA expression. RESULTS: High RACGAP1 mRNA expression (above the median) was associated with poor DFS (log-rank, p = 0.002) and OS (p < 0.001). High histological grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of RACGAP1. Results of the Cox multivariate regression analysis revealed that high RACGAP1 mRNA expression independently predicted poor overall survival (Wald's p = 0.008). High Ki67 protein expression was also an adverse prognostic factor for death (p = 0.016), while high NPI score values were not. CONCLUSIONS: High RACGAP1 mRNA expression, as assessed by qRT-PCR, was found to be of adverse prognostic significance in high-risk early breast cancer patients treated with dose-dense sequential chemotherapy. The utility of RACGAP1 mRNA expression in patient selection for treatment with aggressive chemotherapy regimens should be further explored and validated in larger cohorts.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas Activadoras de GTPasa/genética , Regulación Neoplásica de la Expresión Génica , Antígeno Ki-67/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Selección de Paciente , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Regresión , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Adulto Joven
17.
Cancer Chemother Pharmacol ; 69(2): 533-46, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21901395

RESUMEN

PURPOSE: It is well recognized that breast cancer is a heterogeneous disease. The purpose of the current study was to classify patients according to the immunohistochemical phenotype of their tumors in an effort to evaluate the outcome of the respective groups of patients and specifically of those with triple-negative breast cancer (TNBC) following dose-dense sequential adjuvant chemotherapy. METHODS: A total of 595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel in the context of a randomized study. ER, PgR, HER2, Ki67, EGFR, and CK5 protein expression were evaluated in 298 formalin-fixed paraffin-embedded tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH). HER2 status and Ki67 protein expression differentiated luminal IHC subtypes (luminal B tumors being HER2 and/or Ki67-positive). RESULTS: Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2 enriched, and 36 (12%) as TNBC. The median follow-up time was 97 months. Patients with luminal A tumors had the best prognosis, with improved disease-free survival (log-rank, P = 0.033) and overall survival (P = 0.006) compared with the other three tumor subtypes. The three subtypes had an increased risk for relapse and death compared with luminal A in multivariate analysis, as well. No benefit from paclitaxel treatment was detected in any of the four subtypes or the total cohort. Hierarchical clustering based on mRNA expression of ER, PgR, and HER2 by quantitative RT-PCR identified patient groups that were comparable to the subtypes identified by IHC. CONCLUSIONS: The results of this study confirm that triple negative, luminal B and HER2-enriched phenotypes identified by IHC are of adverse prognostic value in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Análisis por Conglomerados , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Fenotipo , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Investigación Biomédica Traslacional/métodos , Adulto Joven
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