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1.
Ann Oncol ; 28(8): 1817-1824, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28459938

RESUMEN

BACKGROUND: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. PATIENTS AND METHODS: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. RESULTS: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. CONCLUSIONS: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. CLINICALTRIALS.GOV NUMBER: NCT01093235.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Taxoides/uso terapéutico , Neoplasias de la Mama/patología , Ciclofosfamida/uso terapéutico , Docetaxel , Diagnóstico Precoz , Epirrubicina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Genes erbB-2 , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Inducción de Remisión , Análisis de Supervivencia
2.
Oncogene ; 25(20): 2839-49, 2006 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-16407843

RESUMEN

This study provides evidence for the importance of p21(CDKN1A) for the repair of replication-mediated DNA double-strand breaks (DSBs) induced by topoisomerase I. We report that defects of p21(CDKN1A) and p53 enhance camptothecin-induced histone H2AX phosphorylation (gammaH2AX), a marker for DNA DSBs. In human colon carcinoma HCT116 cells with wild-type (wt) p53, gammaH2AX reverses after camptothecin removal. By contrast, gammaH2AX increases after camptothecin removal in HCT116 cells deficient for p53 (p53-/-) or p21(CDKN1A) (p21-/-) as the cells reach the late-S and G2 phases. Since p21-/- cells exhibit similar S-phase arrest as wt cells in response to camptothecin and aphidicolin does not abrogate the enhanced gammaH2AX formation in p21-/- cells, we conclude that enhanced gammaH2AX formation in p21-/- cells is not due to re-replication. The cell cycle checkpoint abrogator and Chk1/Chk2 inhibitor 7-hydroxystaurosporine (UCN-01) also increases camptothecin-induced gammaH2AX formation and inhibits camptothecin-induced p21(CDKN1A) upregulation in HCT116 wt cells. TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling) assays demonstrate that gammaH2AX formation in late S and G2 cells following CPT treatment corresponds to DNA breaks. However, these breaks are not related to apoptotic DNA fragmentation. We propose that p21(CDKN1A) prevents the collapse of replication forks damaged by stabilized topoisomerase I cleavage complexes.


Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/fisiología , Reparación del ADN/fisiología , Replicación del ADN , ADN-Topoisomerasas de Tipo I/farmacología , ADN/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estaurosporina/análogos & derivados , Afidicolina/farmacología , Apoptosis/efectos de los fármacos , Rotura Cromosómica , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , ADN/genética , Daño del ADN/efectos de los fármacos , Células HCT116 , Histonas/metabolismo , Humanos , Etiquetado Corte-Fin in Situ , Fosforilación/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Fase S/efectos de los fármacos , Estaurosporina/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/fisiología
3.
Cancer Chemother Pharmacol ; 55(6): 577-83, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15726367

RESUMEN

Ruthenium(II) organometallic complexes form monofunctional adducts with guanine in DNA in vitro and have a cytotoxic anticancer activity spectrum in preclinical models suggesting lack of cross-resistance with cisplatin. The primary cytotoxic lesion remains to be identified but the downstream mechanism of action is nevertheless of interest. Using isogenic derivatives of the HCT116 colorectal cancer cell line, we investigated the role of p53, p21/WAF1 and Bax in the cellular response to the novel ruthenium(II) organometallic complex RM175, [(eta(6)-C(6)H(5)C(6)H(5))RuCl (H(2)NCH(2)CH(2)NH(2)-N,N')](+) PF(6)(-). Western blotting demonstrated dose-dependent accumulation of p53, Bax and p21/WAF1 within 48 h of the start of RM175 treatment in wild-type HCT116 cells. HCT116 wild-type and Bax-null cells arrested in the G(1) and G(2) phases of the cell cycle. This pattern of cell cycle arrest was not observed in p53-null or in p21/WAF1-null cells. Following RM175 treatment, HCT116 wild-type and p21/WAF1 null cells underwent a dose-dependent induction of apoptosis (Annexin-V and sub-G(1) apoptosis assays). This apoptotic response was not observed in p53-null or Bax-null cells. In short-term sulphorhodamine B assays, the IC(50) for RM175 was 16 microM for p53-null HCT116, and 8 microM for wild-type cells (P<0.05). However, the sensitivity to RM175 in clonogenic assays at 16 days was independent of p53 status. These results identify determinants of the short-term in vitro response to RM175 demonstrating a role for p53 and p21/WAF1 in the growth arrest and for p53 and Bax in the apoptotic response. The mechanism of p53-independent suppression of long-term clonogenicity remains to be determined.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Compuestos Organometálicos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Rutenio/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Supervivencia Celular/efectos de los fármacos , Clonación Molecular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Immunoblotting , Concentración 50 Inhibidora , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína p53 Supresora de Tumor/genética , Proteína X Asociada a bcl-2
4.
Surg Oncol ; 12(4): 289-304, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14998569

RESUMEN

Adjuvant endocrine therapy following surgical resection of early, endocrine sensitive breast cancer has proven benefits in reducing risk of recurrence and death, as demonstrated in many mature well controlled clinical trials. The introduction of new endocrine therapies as potential alternatives to tamoxifen or ovarian ablation and the incorporation of neoadjuvant endocrine therapy into the overall management strategy continue to provide exciting challenges for clinical research. In this article the focus is on as yet unanswered questions pertinent to adjuvant or neoadjuvant endocrine therapy for breast cancer. In the process, we broadly outline the current limits of knowledge as we understand it. Many relevant and current clinical trials are ongoing and a list of these with contact details or references are provided. Definitive data is urgently needed in many areas and, when available, will provide important evidence on which the management of breast cancer patients in future can be based. Participation in relevant clinical trials is vital for future progress.


Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Moduladores de los Receptores de Estrógeno/administración & dosificación , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/prevención & control , Tamoxifeno/administración & dosificación , Adulto , Factores de Edad , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Mastectomía/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Posmenopausia , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
6.
Med Oncol ; 29(2): 755-60, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21286862

RESUMEN

Estimation of renal function is crucial to guidance of systemic chemotherapy. With stable creatinine levels, the glomerular filtration rate (GFR) is often estimated from a single measurement of serum creatinine. We compared accuracy of the Cockroft and Gault (C&G), modifying diet in renal diseases (MDRD) and Wright estimates in Oncology patients with renal impairment. Analysis was carried out on the basis of monodentate platinum treatment as the nephrotoxic mechanism of these drugs may affect accuracy of these estimates. Sixty-two consecutive patients with stable creatinine levels who had isotopic GFR measurement of ≤ 60 ml min(-1) at a regional cancer center were reviewed. Twenty-nine were on monodentate platinum treatment. Isotopic GFR was compared with estimated GFR by the three equations. We defined three categories of estimate based on the fractional difference from isotopic GFR: 'perfect' (< 10%), 'reasonable' (≥ 10% but < 30%) and 'poor' (≥ 30%). There was a trend toward provision of more perfect estimates by the MDRD equation particularly in patients on monodentate platinum treatment. Similar numbers had poor estimates from either of these equations, particularly at extremes of body weight. The MDRD formula may be the most accurate of these equations in Oncology patients with renal impairment, particularly with monodentate platinum treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tasa de Filtración Glomerular , Enfermedades Renales/complicaciones , Modelos Teóricos , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/etiología , Anciano , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Creatinina/sangre , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Renales/tratamiento farmacológico , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos
8.
Br J Cancer ; 63(6): 945-52, 1991 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-2069849

RESUMEN

Between 1979 and 1987 the Scotland and Newcastle Lymphoma Group registered 972 adults with Working Formulation high or intermediate grade non-Hodgkin's lymphoma. Clinical, pathological and investigational data were recorded prospectively on a computer database allowing analysis for prognostic factors. We have derived prognostically important characteristics and have tested prospectively the validity of the prognostic index on a geographically distinct sub-set of patients from the Edinburgh/Borders clinics. Multivariate analysis showed the following factors to be important in declining order of power; advancing age, worsening performance status, CNS/liver involvement, abnormal white cell count, 'B' symptoms and advancing clinical stage. Patient individual scores allowed them to be aggregated into one of three distinct prognostic groupings separated by arbitrary cut-points into a Best Group (39%) where the median survival exceeds 5 years (53% alive at 5 years), an Intermediate Group (30%) with median survival of 21 months (21% alive at 5 years), and a Worst Group (31%) whose median survival is 7 months (8% alive at 5 years). Similar prognostic group separations occurred when analysis was confined to: patients younger than 70 years; patients treated with initial chemotherapy; patients treated with initial radiotherapy; patients within any of the major pathological sub-groups.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Bases de Datos Bibliográficas , Evaluación de Medicamentos , Humanos , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/fisiopatología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Factores de Riesgo
9.
Ann Oncol ; 2(9): 655-62, 1991 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-1742221

RESUMEN

A prognostic model was developed by examination of the prospectively recorded presentation characteristics of patients presenting with low grade non-Hodgkin's lymphomas (LGL). A geographically distinct group (Edinburgh and Borders) was excluded in order to test the validity of the model based on the rest of the Scotland and Newcastle Lymphoma Group (SNLG) population. Between 1979 and 1987 506 patients presented with low grade lymphoma according to Working Formulation definition within one of each of the three main pathology categories. The median available follow-up was 47 months. In a multivariate analysis performance status, age, stage, gender and haemoglobin all contributed separately. 25% of all patients had relatively good prognosis with a median survival not reached and 84% alive at 5 years. Conversely for the worst prognostic group of 25% of patients the median survival is 18 months with only 26% surviving at 5 years. Finally for the intermediate group of 50% of all patients, median survival is 69 months with 58% alive at 5 years. These striking prognostic separations are shown also to be valid in sub-group analysis. Thus young patients within any pathology subgroup have been identified with bad prognostic lymphoma for whom novel strategies in therapy should be devised.


Asunto(s)
Linfoma no Hodgkin/diagnóstico , Anciano , Distribución de Chi-Cuadrado , Femenino , Estudios de Seguimiento , Humanos , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Tasa de Supervivencia
10.
Biophys J ; 69(2): 660-73, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8527680

RESUMEN

A pulsed source neutron spectrometer has been used to measure vibrational spectra (20-4000 cm-1) of dry and hydrated type I collagen fibers, and of two model polypeptides, polyproline II and (prolyl-prolyl-glycine)10, at temperatures of 30 and 120 K. the collagen spectra provide the first high resolution neutron views of the proton-dominated modes of a protein over a wide energy range from the low frequency phonon region to the rich spectrum of localized high frequency modes. Several bands show a level of fine structure approaching that of optical data. The principal features of the spectra are assigned. A difference spectrum is obtained for protein associated water, which displays an acoustic peak similar to pure ice and a librational band shifted to lower frequency by the influence of the protein. Hydrogen-weighted densities of states are extracted for collagen and the model polypeptides, and compared with published calculations. Proton mean-square displacements are calculated from Debye-Waller factors measured in parallel quasi-elastic neutron-scattering experiments. Combined with the collagen density of states function, these yield an effective mass of 14.5 a.m.u. for the low frequency harmonic oscillators, indicating that the extended atom approximation, which simplifies analyses of low frequency protein dynamics, is appropriate.


Asunto(s)
Colágeno/química , Péptidos/química , Secuencia de Aminoácidos , Animales , Fenómenos Biofísicos , Biofisica , Datos de Secuencia Molecular , Estructura Molecular , Neutrones , Dispersión de Radiación , Análisis Espectral , Vibración
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