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1.
Ann Cardiol Angeiol (Paris) ; 69(4): 180-191, 2020 Oct.
Artículo en Francés | MEDLINE | ID: mdl-32854906

RESUMEN

BACKGROUND: The usefulness of the combined assessment of HbA1c and plasma glucose (PG) in acute myocardial infarction (AMI) in non-diabetic patients remains unclear. PURPOSE: In a large observational study, we aimed to identify the prognostic values of these biomarkers regarding one-year all-cause mortality in non-diabetic patients after AMI. METHODS: From the "obseRvatoire des Infarctus de Côte d'Or" (RICO) survey database, we included all consecutive non-diabetic patients with AMI (n=6617) from May 2001 to December 2016. Exclusion criteria were: admission known or unknown diabetes, in-hospital death. The primary endpoint was all-cause one-year mortality. The secondary endpoints were: MACE, infarct size, LVEF<40% and GRACE risk score. Cut-off levels (high/low) were determined by ROC curve analysis for the prediction of one-year death (HbA1c 5.9% and PG 131mg/dL) to set up 4 groups: low HbA1c/low glucose (n=3158), low HbA1c/high glucose (n=1264), high HbA1c/low glucose (n=1378) and high HbA1c/high glucose (n=817). RESULTS: Elevation of PG was associated with elevated rate of LVEF<40%, STEMI, anterior wall location, DFG<60mL/min/m2 and higher troponin Ic pic (all P<0.001); HbA1c>5.9% was associated with elevated rate of CRP>3mg/L (P<0.001); high HbA1c and high PG together were associated with higher rate of MACE (P<0.001). By multivariate logistic regression analysis, elevated admission PG remained a strong predictor of one-year all-cause [OR (95%CI): 1.64 (1.31-2.05)] mortality and cardiovascular mortality [OR (95%CI): 1.75 (1.33-2.31)], beyond GRACE score [OR (95%CI): 1.03 (1.03-1.04)], as well as elevated HbA1c [OR (95%CI): 1.43 (1.15-1.78) and OR (95%CI): 1.83 (1.39-2.41) respectively]. CONCLUSIONS: Admission PG and HbA1c had strong independent predictive value regarding one-year all-cause mortality in our non-diabetic patients with AMI. These biomarkers could be useful to identify the most-at-risk patients after AMI in order to reduce residual risk in this target population.


Asunto(s)
Glucemia/análisis , Hemoglobina Glucada/análisis , Infarto del Miocardio/sangre , Infarto del Miocardio/mortalidad , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Causas de Muerte , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Infarto del Miocardio sin Elevación del ST/sangre , Infarto del Miocardio sin Elevación del ST/mortalidad , Pronóstico , Curva ROC , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/mortalidad , Volumen Sistólico/fisiología , Factores de Tiempo , Troponina I/sangre
2.
J Natl Cancer Inst ; 90(18): 1400-6, 1998 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-9747871

RESUMEN

BACKGROUND: Cellular metabolism in glioblastoma multiforme, the most common primary brain tumor in humans, is characterized by a high rate of aerobic glycolysis that is dependent on mitochondria-bound hexokinase. Moreover, high levels of glucose utilization and tumor aggressiveness in glioblastoma are associated with a high density of mitochondrial benzodiazepine receptors. We sought to inhibit glioblastoma metabolism by simultaneously inhibiting hexokinase with lonidamine and binding benzodiazepine receptors with diazepam. METHODS: Cellular glioblastoma metabolism in five glioblastoma cell lines was assessed in vitro by measuring cell proliferation (by use of a tetrazolium-based colorimetric assay, measurement of DNA synthesis, and assessment of cell cycle distribution), by measuring membrane fluidity (by fluorescence polarization measurement of cells stained with a fluorescent probe), and by measuring changes in intracellular pH. Immunodeficient nude mice bearing subcutaneous xenografts of human glioblastoma cells were used to assess the antitumor activities of lonidamine and diazepam; the mice were treated twice daily with lonidamine (total daily dose of 160 mg/kg body weight) and/or diazepam (total daily dose of 1 mg/kg body weight) for 10 consecutive days. RESULTS: When used in combination, the two drugs had a stronger effect on glioblastoma cell proliferation and metabolism in vitro than did either agent used alone. In vivo, the combination of lonidamine and diazepam was significantly more effective in reducing glioblastoma tumor growth than either drug alone (two-sided P<.01, Mann-Whitney U test, comparing growth of treated tumors with that of untreated tumors); this tumor growth retardation was maintained as long as treatment was given. CONCLUSION: The combination of lonidamine and diazepam--drugs that target two distinct mitochondrial sites involved in cellular energy metabolism--potentiates the effects of the individual drugs and may prove useful in the treatment of human glioblastomas.


Asunto(s)
Ansiolíticos/farmacología , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Diazepam/farmacología , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Indazoles/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Animales , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Sinergismo Farmacológico , Citometría de Flujo , Fluorescencia , Humanos , Ratones , Ratones Desnudos , Timidina/metabolismo , Resultado del Tratamiento , Células Tumorales Cultivadas
3.
Oncogene ; 20(2): 260-9, 2001 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-11313953

RESUMEN

Procaspase-2 is one of the cysteine aspartate proteases involved in apoptotic cell death. Alternative splicing of CASP-2 messenger RNA generates a long isoform, procaspase-2L, whose overexpression induces cell death and a truncated isoform, procaspase-2S, whose function remains poorly defined. The present study explored the consequences of procaspase-2S overexpression in U937 human leukemic cells exposed to the topoisomerase II inhibitor etoposide as an apoptotic stimulus. Overexpression of procaspase-2S in U937 cells partially prevented nuclear changes associated with etoposide-induced cell death, as determined by Hoechst 33342 staining of nuclear chromatin and electron microscopy studies. Procaspase-2S also prevented the maturation of apoptotic bodies, delayed phosphatidylserine externalization on the plasma membrane and prevented the cleavage and activation of procaspase-2L. These effects were not observed when the cysteine 289 in the consensus QACRG motif was mutated into a serine. Wild-type procaspase-2S overexpression did not influence the cleavage of procaspase-3, procaspase-7 and poly(ADP-ribose)polymerase nor the fragmentation of nuclear DNA into nucleosome-sized fragments. Altogether, these results indicate that the short isoform of procaspase-2 negatively interferes with selective features of apoptosis, an activity that is suppressed by mutation of the cysteine 289.


Asunto(s)
Apoptosis/fisiología , Caspasas/metabolismo , Cromatina/ultraestructura , Precursores Enzimáticos/metabolismo , Fosfatidilserinas/metabolismo , Secuencias de Aminoácidos , Apoptosis/efectos de los fármacos , Secuencia de Bases , Caspasa 2 , Caspasas/genética , Cisteína , Fragmentación del ADN , Inhibidores Enzimáticos/farmacología , Precursores Enzimáticos/genética , Etopósido/farmacología , Humanos , Isoenzimas , Leucemia , Datos de Secuencia Molecular , Mutación , Inhibidores de Topoisomerasa II , Transfección , Células Tumorales Cultivadas
4.
Biochim Biophys Acta ; 1586(3): 233-42, 2002 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-11997075

RESUMEN

The molecular basis of the intrinsic vulnerability of the compliant right ventricle to chronic pressure overload is poorly understood. Extensive apoptosis, possibly coupled with aberrant cell cycle reentry, in response to unrestrained biomechanical stress may account for this phenotypic flaw. To address this issue we have studied changes in expression of the cell cycle and apoptosis regulators in the right ventricle following induction of pulmonary hypertension in the rat by injection of monocrotaline. Hypertrophy, apoptosis and cell cycle events, as well as expression of their regulator genes were documented during a period of 31 days. The hypertrophy index reached 127% at day 31. At the early stage both apoptosis and cell proliferation pathways were coincidentally activated. The level of cyclin A and E transcripts steadily increased, the labeling index was 4.8% at day 31, and expression of the caspase-3 gene peaked at day 14. Until day 21 execution of apoptosis was prevented, probably by a high level of Bcl-2. At this time point Bcl-2 collapsed, cyclin D1 was upregulated, the differentiation gatekeeper p27Kip1 was downregulated, pro-caspase-3 was activated and extensive apoptosis developed. These results indicate that the right ventricle is especially vulnerable to apoptotic pressure-dependent stimuli, and that the cell cycle and apoptosis pathways were co-activated in this experimental model.


Asunto(s)
Apoptosis/fisiología , Corazón/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Miocardio/patología , Angiotensina II/metabolismo , Animales , Apoptosis/genética , Ciclo Celular/genética , Ciclo Celular/fisiología , Modelos Animales de Enfermedad , Ventrículos Cardíacos , Hipertrofia Ventricular Izquierda/etiología , Inmunohistoquímica , Miocardio/metabolismo , Presión , ARN Mensajero/análisis , Ratas , Receptor de Angiotensina Tipo 1 , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
Clin Cancer Res ; 6(2): 643-53, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10690550

RESUMEN

Efficacy of chemotherapy is limited in numerous tumors by specific cellular mechanisms that inactivate cytotoxic antitumoral drugs, such as ATP-dependent drug efflux and/or drug detoxification by glutathione. In reducing ATP pools and/or glutathione synthesis, it might be possible to enhance the efficacy of drugs affected by such resistance mechanisms. Reduction of the ATP pool and glutathione content is achievable in cancer cells by depleting the exogenous methionine (Met) supply and ethionine. Thus, the rationale for the present study was to use Met depletion to decrease the ATP and glutathione pools so as to sensitize tumors refractory to cytotoxic anticancer drugs. Met depletion was achieved by feeding mice a methionine-free diet supplemented with homocysteine. The effects of Met depletion combined with ethionine and/or chemotherapeutic agents were studied using human solid cancers xenografted into nude mice. TC71-MA (a colon cancer) SCLC6 (a small cell lung cancer), and SNB19 (a glioma) were found to be refractory to cisplatin, doxorubicin, and carmustine, respectively. These three drugs are used to treat such tumors and are dependent for their activity on the lack of cellular ATP- or glutathione-dependent mechanisms of resistance. TC71-MA, SCLC6, and SNB19 were Met dependent because their proliferation in vitro and growth in vivo were reduced by Met depletion. Cisplatin was inactive in the treatment of TC71-MA colon cancer, whereas a methionine-free diet, alone or in combination with ethionine, prolonged the survival of mice by 2-fold and 2.8-fold, respectively. When all three approaches were combined, survival was prolonged by 3.3-fold. Doxorubicin did not affect the growth of SCLC6, a MDR1-MRP-expressing tumor. A Met-deprived diet and ethionine slightly decreased SCLC6 growth and, in combination with doxorubicin, an inhibition of 51% was obtained, with survival prolonged by 1.7-fold. Combined treatment produced greater tumor growth inhibition (74%) in SCLC6-Dox, a SCLC6 tumor pretreated with doxorubicin. Growth of SNB19 glioma was not inhibited by carmustine, but when it was combined with Met depletion, survival duration was prolonged by 2-fold, with a growth inhibition of 80%. These results indicate the potential of Met depletion to enhance the antitumoral effects of chemotherapeutic agents on drug-refractory tumors.


Asunto(s)
Antineoplásicos/uso terapéutico , Suplementos Dietéticos , Resistencia a Múltiples Medicamentos , Etionina/uso terapéutico , Homocisteína/administración & dosificación , Metionina/deficiencia , Neoplasias/tratamiento farmacológico , Transportadoras de Casetes de Unión a ATP/genética , Adenosina Trifosfato/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , División Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Femenino , Genes MDR , Glioma/tratamiento farmacológico , Glutatión/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Ratones Desnudos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Neoplasias/patología , Transcripción Genética , Trasplante Heterólogo , Células Tumorales Cultivadas
6.
Eur J Cancer ; 31A(11): 1862-8, 1995 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8541114

RESUMEN

Small cell lung carcinomas (SCLC) are characterised by chemosensitivity to diverse antitumoral compounds. However, responses are transitory and relapses are commonly observed. We examined the ability of verapamil, a reverser of P-glycoprotein (Pgp)-related resistance, to improve the efficacy of CyCAV combined chemotherapy (Cy, cyclophosphamide (CPA); C, cisplatin (CDDP); A, doxorubicin (ADM);V, etoposide (VP16)), as currently administered to SCLC patients at Institut Gustave-Roussy, France, and adapted to the treatment of nude mice implanted with these tumours. Although Pgp encoded by the MDR1 (multidrug resistance) gene is not the only mechanism for multidrug resistance (MDR), and not all drugs included in this regimen are recognised by Pgp, we anticipated a therapeutic benefit. Four different SCLC lines, expressing the MDR1 gene and recently grafted into nude mice, were used. SCLC-75, SCLC-6 and SCLC-41 originated from untreated patients, and SCLC-74T was derived from a patient treated with a combination of ADM, CPA and VP16. SCLC-41% and SCLC-6T tumours were used after having undergone, respectively, five and nine cycles of in vivo passage and CyCAV treatment of the tumour-bearing nude mice, to reinforce their chemoresistance. The efficacy of the CyCAV regimen, associated with or without verapamil (given 24 h before CyCAV on days 1-5), was tested on the growth of these SCLC. Verapamil (25 mg/kg) improved the antitumour effect of CyCAV in mice bearing SCLC-6T, SCLC-41T and SCLC-75 tumours, although toxicity was observed. Verapamil modestly delayed the plasma clearance of ADM. Two daily injections of 10 mg/kg of verapamil, administered at a 3 h interval, proved to be effective, whereas the same total dose administered as a bolus was not. These results indicate that the association of some reversers of MDR, including drugs possibly interacting with Pgp, might potentiate SCLC combined chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Resistencia a Múltiples Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Verapamilo/uso terapéutico , Animales , Carcinoma de Células Pequeñas/patología , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos , Quimioterapia Combinada , Etopósido/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo
7.
Cancer Lett ; 130(1-2): 133-41, 1998 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-9751266

RESUMEN

Intrinsic or acquired drug resistance is a major limiting factor of the effectiveness of chemotherapy. Increased expression of either the MRP gene or the MDR1 gene has been demonstrated to confer drug resistance in vitro. In this study, we examined MRP and MDR1 gene expression in a panel of 17 small cell lung cancers (SCLC) xenografted into nude mice from treated and untreated patients using an RT-PCR technique. For some of them, the outcome of the corresponding patients was known and we related MDR1/MRP expression with the xenograft response to C'CAV (cyclophosphamide, cisplatin, adriamycin and etoposide) combined chemotherapy. Fifteen (88%) of the 17 cases of SCLC were found to be positive for either MDR1 or MRP. MRP gene expression was present in 12 (71%) of 17 cases, whereas MDR1 gene expression was detected in eight (50%) of 16 cases. For six SCLC, the survival duration of patients differed, with three patients surviving for more than 30 months after therapy. Among these six turnours, five expressed MRP and/or MDR1. These six xenografts responded to the C'CAV treatment but a significant rate of cure was obtained in only three cases. No obvious relationship was observed between the response to this treatment and MRP or MDR1 expression. However, the remarkably high levels and frequency of MRP expression in some SCLC samples indicate that future developments in chemotherapy of this tumour type should anticipate that drugs which are substrates of MRP may be of limited effectiveness.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Carcinoma de Células Pequeñas/genética , Genes MDR/genética , Neoplasias Pulmonares/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/metabolismo , Cisplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos/genética , Etopósido/administración & dosificación , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , ARN Mensajero/metabolismo , Trasplante Heterólogo
8.
Biochem Pharmacol ; 56(4): 497-502, 1998 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-9763226

RESUMEN

Inherent or acquired resistance to multiple natural drugs, termed multidrug resistance (MDR), represents a major obstacle to chemotherapy. Expression of P-glycoprotein (P-gp) in MCF7mdr and MCF7R resistant cells was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. MCF7R, but not the MDR1 gene-transfected MCF7mdr cells, expressed multidrug-related protein (MRP) concomitantly. Efficacy of an MDR modulator, designated as Servier 9788 (S9788), was estimated by doxorubicin (Dox) sensitization, Dox incorporation, and functional rhodamine 123 assay on MCF7 cell lines. Results showed that S9788 modulates the P-gp-associated MDR of MCF7mdr cells as well as the Multidrug-related protein-associated MDR of MCF7R cells.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Transportadoras de Casetes de Unión a ATP/fisiología , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Piperidinas/farmacología , Triazinas/farmacología , Doxorrubicina/farmacocinética , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Rodamina 123 , Rodaminas/metabolismo , Células Tumorales Cultivadas
9.
Virchows Arch ; 435(5): 509-19, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10592055

RESUMEN

Previous studies showed that the hormone relaxin acts on human breast cancer MCF-7 cells in vitro by modulating cell proliferation and promoting cell differentiation toward a duct epithelial phenotype. The present study was designed to investigate whether relaxin retains these properties when acting in vivo on MCF-7 cell tumors developed in athymic nude mice. Mice bearing MCF-7 cell tumors transplanted under the mammary fat pad and estrogenized to sustain tumor growth were treated systemically with relaxin (10 microg/day) for 19 days. Vehicle-treated mice were used as controls. Thirty days later, the mice were sacrificed and tumor fragments were analyzed by light and electron microscopy and immunocytochemistry. Measurements of tumor volume were recorded weekly for the overall experimental period. The results obtained indicate that relaxin treatment promotes differentiation of tumor cells towards both myoepithelial-like and epithelial-like cells, as judged by the ultrastructural features of the cells and by the increased expression of smooth muscle actin and cadherins. Measurements of tumor size and of the number of cycling cells show that relaxin, at the doses and times of exposure used in this study, does not significantly influence tumor growth and cell proliferation.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/ultraestructura , Relaxina/farmacología , Actinas/biosíntesis , Animales , Cadherinas/biosíntesis , División Celular/efectos de los fármacos , Femenino , Humanos , Inmunohistoquímica , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Desnudos , Microscopía Electrónica , Trasplante de Neoplasias , Fenotipo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Células Tumorales Cultivadas
10.
Life Sci ; 60(12): 919-31, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9061049

RESUMEN

Growth of numerous malignant tumors depends on an exogenous methionine (MET) supply, while endogenously synthesized MET supports normal cell proliferation. Because an antitumor effect should be obtained by aggravating the altered MET metabolism in gliomas, MET dependency of human xenografted gliomas was evaluated and a therapeutic approach using MET deprivation or MET analogs to induce MET starvation was applied. In vitro proliferation inhibition of glioma cell lines by MET deprivation and two MET analogs, ethionine (ETH) and trifluoromethylhomocysteine (TFH), was measured. Proliferation of 7 human glioma cell lines tested was inhibited in MET-free medium, and was poorly or not reversed by homocysteine (HCY). ETH or TFH (concentration range: 0.005-2 mg/ml) inhibited proliferation of all cell lines tested. MET analog-induced inhibition was abolished by MET and enhanced by HCY. Cell-cycle alterations due to MET deprivation were optimally assessed after 30 h of culture and bromodeoxyuridine incorporation. In MET- medium, cells were arrested in the G1-phase. ETH induced a dramatic accumulation of cells in the G2-phase. ATP contents were reduced by MET analogs only in HCY+ medium, suggesting complementary effects of MET analogs and HCY. Human glioma bearing nude mice were fed an amino acid-substituted MET- HCY-supplemented diet (MET-HCY+) and/or treated with MET analogs, injected intraperitoneally daily. Using two human xenografted tumors derived from gliomas, antitumor effects were obtained by subjecting tumor-bearing nude mice to MET starvation. TG-1-MA was more sensitive to MET depletion (40% of growth inhibition, P < 0.10) than TG-8-OZ (no growth inhibition). Antitumor effects of a MET-HCY+ diet and 200 mg/kg of ETH were potentiated when co-administered to glioma-bearing mice (77% GI, P < 0.025 and 67%, P < 0.0057 to TG-1-MA and TG-8-OZ respectively). A dose-response effect with no toxicity was obtained when the ETH dose was increased 10 fold. Potentiation of the effects of ETH and a MET-free diet indicates that they probably act on the same pathway but not the same target. In conclusion, experimentally induced MET deprivation and MET-analog treatment retarded the growth of human gliomas. Combination of MET-analog therapy with MET substitution by HCY enhanced their respective effects.


Asunto(s)
Glioma/metabolismo , Metionina/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacología , Ciclo Celular , División Celular/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Homocisteína/farmacología , Humanos , Metionina/análogos & derivados , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Trasplante Heterólogo
11.
Anticancer Res ; 17(5A): 3393-401, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9413178

RESUMEN

Various cytoskeleton modifications are associated with malignant cell transformation and have been used as prognostic factors. A human breast cancer cell line (MCF7S) and its multidrug resistant (MDR) subline (MCF7R) were characterized here for their intermediate filaments (IFs) expression (cytokeratin 8, 18, 19 and vimentin) as a function of their resistance phenotype. Modifications of these cytoskeleton molecules were analyzed by flow cytometry, immunofluorescence, electrophoresis and immunoblotting techniques. Cytokeratins 8 and 18 were similarly expressed in the cell lines. Cytokeratin 19 was expressed in the MCF7S cell line and not in the MCF7R variant, while vimentin was highly expressed in MCF7R and slightly in MCF7S. Analysis of IFs after the addition of doxorubicin (Dox) in the culture medium of MCF7S, showed an increase in cytokeratin 8 filaments. Vimentin expression in MCF7R was not modified in the presence of these different MDR modulators. Acquisition of MDR was associated with an increase and a redistribution of vimentin filaments characterized by a perinuclear polarization. These drug resistance associated changes might derive from different biological processes triggered by chemotherapy. In conclusion, this suggests that this intermediate filament could be a marker associated with chemoresistance or a marker of malignancy in certain epithelial cancers.


Asunto(s)
Neoplasias de la Mama/ultraestructura , Citoesqueleto/ultraestructura , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Vimentina/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Neoplasias de la Mama/patología , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/farmacología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Regulación Neoplásica de la Expresión Génica , Genes MDR , Humanos , Queratinas/metabolismo , ARN Mensajero/genética , ARN Neoplásico/genética , Células Tumorales Cultivadas
12.
Bull Cancer ; 87 Spec No: 7-22, 2000 Dec.
Artículo en Francés | MEDLINE | ID: mdl-11250604

RESUMEN

Aromatase is an enzymatic complex responsible for the conversion of androgens into estrogens; these hormones are important in development, reproduction, but also in the growth of estrogen-dependent cancer. This enzyme is present in 60-70% of the breast cancer. The aromatase inhibitors are important drugs in the breast cancer treatment of postmenopausal women. In order to study their in vivo activity, animal models have been developed, e.g. rat with tumour induced by 7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice with aromatase transfected MCF-7 xenograft. In this review, we were interested in preclinical results obtained with both classes: steroidal and nonsteroidal inhibitors. The former group, as substrate analogs formestane or exemestane, are irreversible, selective and long-lasting inhibitors of aromatase. The nonsteroidal molecules, such as letrozole or anastrozole, are reversible inhibitors with high affinity. Finally, knowledge of the enzyme active site, with molecular modeling and site-directed mutagenesis, could be useful to develop new inhibitor families, more specific and potent in vivo.


Asunto(s)
Androstenodiona/análogos & derivados , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa , Inhibidores Enzimáticos/uso terapéutico , Aminoglutetimida/uso terapéutico , Anastrozol , Androstadienos/uso terapéutico , Androstenodiona/uso terapéutico , Animales , Aromatasa/fisiología , Evaluación Preclínica de Medicamentos , Fadrozol/uso terapéutico , Femenino , Humanos , Letrozol , Modelos Animales , Nitrilos/uso terapéutico , Ratas , Relación Estructura-Actividad , Triazoles/uso terapéutico
13.
Blood ; 97(6): 1835-44, 2001 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11238127

RESUMEN

Engagement of the plasma membrane receptor Fas can induce apoptosis of leukemic cells. Signaling through Fas requires the formation of a death-inducing signaling complex (DISC) that involves the cytoplasmic domain of Fas, the adaptor molecule FADD/MORT-1, and procaspase-8. The present study investigated whether another caspase, known as procaspase-2L, played a role in Fas-mediated cell death. A series of human leukemic variant cells was derived by stable transfection with a CASP2L antisense construct (CASP2L/AS). Specific down-regulation of procaspase-2L decreased the sensitivity of these cells to apoptosis induced by an agonistic anti-Fas antibody (Ab, clone CH11), as determined by studying DNA fragmentation, chromatin condensation, and externalization of phosphatidylserine on the plasma membrane. In leukemic cells transfected with an empty vector, anti-Fas Ab treatment activated caspase-8, decreased the expression of the BH3 domain-only protein Bid, triggered the release of cytochrome c from the mitochondria to the cytosol, and activated caspase-3. All these events could not be observed when CASP2L/AS cells were similarly treated with anti-Fas Abs. CASP2L/AS transfection did not inhibit the formation of the DISC and no direct interaction between procaspase-2L and either Fas or FADD or procaspase-8 was identified. Down-regulation of procaspase-2L inhibited anti-Fas Ab-mediated cleavage of c-FLIP (FLICE-inhibitory protein), a protein that interferes with the formation of a functional DISC. These results suggest that the long isoform of caspase-2 plays a role in the Fas-mediated pathway to cell death by contributing to caspase-8 activation at the DISC level.


Asunto(s)
Apoptosis/efectos de los fármacos , Caspasas/fisiología , Péptidos y Proteínas de Señalización Intracelular , Leucemia/tratamiento farmacológico , Receptor fas/farmacología , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/metabolismo , Caspasa 2 , Caspasa 3 , Caspasa 8 , Caspasa 9 , Caspasas/efectos de los fármacos , Caspasas/genética , Caspasas/metabolismo , Caspasas/farmacología , Grupo Citocromo c/efectos de los fármacos , Grupo Citocromo c/metabolismo , ADN sin Sentido/farmacología , Humanos , Leucemia/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/farmacología , Isoformas de Proteínas/fisiología , Transfección , Células Tumorales Cultivadas
14.
Br J Cancer ; 75(11): 1605-12, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9184175

RESUMEN

Methionine (MET) is required for cell metabolism. MET endogenously synthesized from homocysteine (HCY) supports the proliferation of normal cells, but not that of numerous malignant cells, as shown previously. MET starvation should have an anti-tumour effect, and its deleterious effects on the hosts might be prevented by HCY. Anti-tumour effects of MET starvation must be reinforced by ethionine (ETH), a MET analogue. MET dependency of PC-3, a human prostate cancer cell line, was studied in vitro. Proliferation of PC-3 cells, cultivated in MET-free medium, was 29% compared with growth in MET+HCY- medium. Addition of HCY to MET-free medium increased the proliferation rate to 56%. The concentration of ETH required to decrease the PC-3 cell proliferation rate to 50% (IC50) was 0.5 mg ml(-1) in MET-HCY- medium. ETH-induced inhibition was abolished by MET addition and was reinforced by HCY. PC-3 cell cycle was blocked in the S-G2-phase after 30 h culture in the absence of MET; this blockage was not reversed by addition of HCY. ETH at the IC50 in MET-HCY+ medium blocked DNA replication. Apoptotic cells appeared after 30 h incubation in MET-HCY+ medium only when ETH was added. ATP pools were decreased after 15 h of culture in MET-free medium. In vivo, MET starvation was obtained by feeding tumour-bearing mice a diet containing a synthetic amino acid mixture as the protein supply, in which HCY replaced MET. Given to nude mice bearing xenografted PC-3, from day 1 after grafting and for 3 weeks, this diet inhibited tumour growth (34% on day 20, P < 0.007); this effect was potentiated by ETH (200 mg kg(-1) day(-1) i.p.) (56% on day 20, P < 5 x 10(-5)). The differences between the effects of these two treatments were significant (P < 0.017) and optimal on day 20. These data showed that combination of ETH and HCY slowed the proliferation of prostate cancer cells in vitro and in vivo, decreased ATP synthesis and caused cell cycle arrest and apoptosis. Experimental therapy based on cancer cell MET metabolism deficiency could be efficient for treating advanced prostate cancers refractory to current therapies.


Asunto(s)
Etionina/uso terapéutico , Metionina/fisiología , Neoplasias de la Próstata/terapia , Adenosina Trifosfato/análisis , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Homocisteína/farmacología , Humanos , Masculino , Metionina/deficiencia , Ratones , Trasplante de Neoplasias , Neoplasias de la Próstata/patología , Trasplante Heterólogo , Células Tumorales Cultivadas
15.
Pathol Biol (Paris) ; 51(1): 1-4, 2003 Feb.
Artículo en Francés | MEDLINE | ID: mdl-12628285

RESUMEN

Prostate cancer is the second cause of cancer death in men. Often, initialy hormono-independent, escape from anti-androgen therapy is a key event of tumoral progression showing an hormone-independent phenotype. To study morphological, genetic and molecular bases associated with the hormono-dependence escape, a new model of human adenocarcinoma prostate xenograft, PAC120, was established with its hormono-dependent and independent variants. Its growth was strongly inhibited by surgical castration or by administration of the new gonadotrophin-releasing hormone antagonist, FE 200486 (Ferring, San Diego, CA). Evolution to hormono-independence was frequently associated with a mucoid differentiation or a neuroendocrine-like pattern, with the apparition of new chromosomic alterations and variations of human gene expressions. PAC120 xenograft is a new model of hormone-dependent prostate cancer, opening the opportunity to study the hormone dependence escape mechanism and to evaluate the efficacity of new therapeutics.


Asunto(s)
Adenocarcinoma , Paclitaxel/análogos & derivados , Neoplasias de la Próstata , Taxoides , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Docetaxel , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Humanos , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Paclitaxel/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Trasplante Heterólogo
16.
Am J Pathol ; 159(2): 753-64, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11485933

RESUMEN

We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient's tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp(6)-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp(6)-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism.


Asunto(s)
Aberraciones Cromosómicas , Neoplasias de la Próstata/fisiopatología , Neoplasias de la Próstata/terapia , Animales , División Celular , Mapeo Cromosómico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Genes erbB-2 , Antagonistas de Hormonas/uso terapéutico , Humanos , Inmunohistoquímica , Cariotipificación , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Metástasis de la Neoplasia , Oligopéptidos/uso terapéutico , Orquiectomía , Polimorfismo Genético , Antígeno Prostático Específico/análisis , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Eliminación de Secuencia , Transcripción Genética , Trasplante Heterólogo
17.
Gastroenterology ; 120(4): 874-88, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11231942

RESUMEN

BACKGROUND & AIMS: Butyrate, produced in the colon lumen, maintains mucosal cell homeostasis. Poorly diffusible, its access is compromised in growing colon cancers and absent in distant metastases. Butyrate regulates DNA synthesis. We postulated that systemic administration of butyrate should reduce colon cancer growth and enhance 5-fluorouracil (5-FU) efficacy. METHODS: A stable derivative of butyrate (3n-But) was used. The antitumoral efficacy of 5-FU and 3n-But, alone or combined, was evaluated in human colorectal cancers (hCRCs) subcutaneously, orthotopically, or intrasplenically grafted into nude mice. Thymidylate synthase (TS) and thymidine kinase (TK) mRNA expression, proliferation, apoptosis, and cell cycle alterations were studied. RESULTS: In vivo, 5-FU alone inhibited growth of only 3 of the 12 hCRCs tested and 3n-But alone had no effect; the 5-FU/3n-But combination inhibited growth of all 16 hCRCs tested. The hCRCs differed in their p53 and microsatellite instability status. 5-FU/3n-But decreased TK and TS mRNA expression by 20- and 40-fold, respectively, and TS activity by 75%, stopped cell proliferation without affecting cell differentiation, and significantly enhanced apoptosis. 3n-But potentiated the efficacy of Tomudex and methotrexate, 2 TS inhibitors, but not that of oxaliplatin. In vitro, 5-FU/3n-But inhibited [3H]thymidine but not bromodeoxyuridine incorporation and induced apoptosis in hCRC cell lines. Cells treated with 5-FU/3n-But did not accumulate in G1 nor in S phase of the cell cycle, while 5-FU and 3n-But arrested the cycle in S and in G1 phase, respectively. 3n-But prevented the cell rescue from 5-FU-induced cytotoxicity by uridine or thymidine. CONCLUSIONS: 3n-But and TS inhibitors acted synergistically against colorectal cancers, independently of the genetic alterations of the hCRCs. The mechanism of action of 5-FU/3n-But could be enhanced reduction of TS and prevention of thymidine salvage in DNA synthesis.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , ADN/biosíntesis , Fluorouracilo/administración & dosificación , Animales , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores , Butiratos/administración & dosificación , Butiratos/farmacología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Dihidrouracilo Deshidrogenasa (NADP) , Sinergismo Farmacológico , Femenino , Fluorouracilo/farmacología , Glucosa/administración & dosificación , Glucosa/análogos & derivados , Glucosa/farmacología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Masculino , Metotrexato/administración & dosificación , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Oxidorreductasas/metabolismo , Proteínas Tirosina Quinasas/genética , Quinazolinas/administración & dosificación , ARN Mensajero/metabolismo , Tiofenos/administración & dosificación , Timidilato Sintasa/genética , Timidilato Sintasa/metabolismo , Trasplante Heterólogo
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