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1.
Scand J Clin Lab Invest ; 67(4): 402-12, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17558895

RESUMEN

Seventy-one cases that had resulted borderline for HER-2 protein expression at conventional immunohistochemical assay (2+) were assessed for HER-2 gene amplification by real-time PCR and by FISH in accordance with the manufacturer's recommendations (gene amplification with ratio >or=2 in both methods). Thirty-three out of 71 cases (47%) resulted amplified at real-time PCR analysis, whereas 15 cases resulted positive at FISH (21%). Apparently, PCR was more sensitive than FISH in HER-2 determination, only 10 cases resulting amplified in both tests. When the mean ratio value obtained in all PCR experiments was adopted as threshold in determining HER-2 gene amplification, the apparent sensitivity of PCR was reduced but correlation between PCR and FISH results was dramatically increased. Furthermore, when the mean PCR ratio value observed in the FISH-positive group was chosen as threshold, the best agreement between PCR and FISH results was achieved. Therefore, we found that the proposed threshold ratio value of >or=2 is not accurate in separating HER-2 amplified and non-amplified cases. We suggest that the threshold ratio value in PCR tests should be determined in each laboratory using FISH controlled cases. Finally, above certain in-lab generated threshold values, PCR might be proposed as a highly predictive positive test in HER-2 assessment.


Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Amplificación de Genes , Receptor ErbB-2/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Persona de Mediana Edad , Adhesión en Parafina , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
2.
Apoptosis ; 10(6): 1445-56, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16215689

RESUMEN

There is a lot of interest in the health benefits of dietary carotenoids and on the relationship of these compounds with smoke. In particular, it is unknown if the enhanced cancer risk observed in smokers following beta-carotene supplementation can be also found using other carotenoids. Here, we studied the effects of the tomato carotenoid lycopene on molecular pathways involved in cell cycle progression, apoptosis and survival in immortalized RAT-1 fibroblasts exposed to cigarette smoke condensate (TAR). Lycopene (0.5-2.0 microM) inhibited cell growth in a dose-and time-dependent manner, by arresting cell cycle progression and by promoting apoptosis in cells exposed to TAR. The arrest of cell cycle was independent of p53 and of 8-OH-dG DNA damage and related to a decreased expression of cyclin D1. Moreover, the carotenoid up-regulated apoptosis and down-regulated the phosphorylation of AKT and Bad in cells exposed to TAR. Such an effect was associated to an inhibition of TAR-induced expression of Cox-2 and hsp90, which is known to maintain AKT activity. This study suggests that lycopene, differently from beta-carotene, can exert protective effects against cigarette smoke condensate.


Asunto(s)
Apoptosis/efectos de los fármacos , Carotenoides/farmacología , Ciclina D1/metabolismo , Fibroblastos/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Humo/efectos adversos , Proteína Letal Asociada a bcl/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular Transformada , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Licopeno , Fosfoproteínas/metabolismo , Ratas , Fumar/efectos adversos , Nicotiana , Proteína p53 Supresora de Tumor/metabolismo
3.
Phytother Res ; 19(2): 152-7, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15852493

RESUMEN

Certain jaesekanadiol p-hydroxy- and p-methoxybenzoates - typical of Ferula communis and Ferula arrigonii sardinian plants - show antiproliferative activity on human colon cancer less. The inhibitory doses 50%, calculated after 72 h of treatment, revealed that the antiproliferative capacity of the compounds was in the following descending order: ferutinin > 2alpha-OH-ferutidin > ferutidin > siol anisate > lapiferin > jaeskeanadiol. Evidence is presented that interaction with type II estrogen-binding sites (EBS) underlies this activity.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Proliferación Celular/efectos de los fármacos , Ferula , Fitoterapia , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico
4.
Neurology ; 64(3): 536-8, 2005 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-15699390

RESUMEN

Morphologic findings of thymuses from 32 anti-acetylcholine receptor (AChR)-negative myasthenia gravis patients, 12 with and 20 without antibodies against the muscle-specific kinase (MuSK), were compared with those from 30 AChR-positive subjects. In contrast with the high frequency of thymic hyperplastic changes in AChR-positive patients, in MuSK-positive subjects histologic alterations were minimal, arguing against an intrathymic disease pathogenesis. Since hyperplastic changes were seen in 35% of MuSK-negative patients, the thymus could be involved in some of these cases.


Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Miastenia Gravis/inmunología , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores Colinérgicos/inmunología , Timo/patología , Adolescente , Adulto , Especificidad de Anticuerpos , Atrofia , Niño , Femenino , Humanos , Hiperplasia , Subgrupos Linfocitarios/inmunología , Masculino , Miastenia Gravis/clasificación , Miastenia Gravis/patología , Miastenia Gravis/cirugía , Método Simple Ciego , Timectomía , Timo/inmunología , Timo/cirugía
5.
Mol Hum Reprod ; 10(9): 665-9, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15286211

RESUMEN

In trophoblast cells exposed to homocysteine (Hcy) we observed cellular apoptosis and the inhibition of trophoblast functions. Because folate and Hcy, linked in the same metabolic pathway, are inversely related, we investigated the role of folic acid in reversing the Hcy effect in human placenta. In primary trophoblast cells we examined the cytosolic release of cytochrome c, both M30 and terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling (TUNEL) and DNA laddering. Hcy (20 micromol/l) treatment resulted in cytochrome c release from mitochondria to the cytosol, and an increased number of M30-positive trophoblast cells and TUNEL positive nuclei. Furthermore, DNA cleavage in agarose gel and the determination of histone-associated DNA fragments have been investigated. Homocysteine induced DNA fragmentation and significantly reduced hCG secretion. The addition of folic acid (20 nmol/l) resulted in inhibition of the effects of Hcy on human trophoblast. These results suggest a protective role of folic acid in the prevention of trophoblast apoptosis linked to Hcy.


Asunto(s)
Apoptosis/fisiología , Ácido Fólico/farmacología , Homocisteína/farmacología , Trofoblastos/efectos de los fármacos , Trofoblastos/fisiología , Células Cultivadas , Gonadotropina Coriónica/metabolismo , Fragmentación del ADN , Femenino , Ácido Fólico/metabolismo , Homocisteína/metabolismo , Humanos , Etiquetado Corte-Fin in Situ , Placenta/metabolismo , Trofoblastos/citología
6.
Leukemia ; 18(8): 1373-9, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15190260

RESUMEN

Cyclooxygenase (COX)-1 or -2 and specific prostaglandin (PG) synthases catalyze the formation of various PGs. We investigated the expression and activity of COX-1 and -2 during granulocyte-oriented maturation induced by all-trans-retinoic acid (ATRA) of NB4 cells, originated from a human acute promyelocytic leukemia (APL), and in blasts from APL patients. The expression of COX isoenzymes or prostaglandin synthases was also investigated in circulating granulocytes and human bone marrow. COX-1 was expressed and enzymatically active in NB4 cells and primary blasts. COX-1 mRNA and protein were induced by ATRA. COX-1 protein increased approximately 2-3.5-fold by culture day 3 in NB4 cells and primary blasts, while basal COX-2 expression was very low and unaffected by ATRA. COX-1-dependent PGE(2) biosynthesis increased during differentiation approx. 5-fold. Indomethacin and the selective COX-1 inhibitor SC-560, but not selective COX-2 inhibition, impaired NB4 differentiation, reducing NADPH-oxidase activity, CD11b and CD11c expression. The immunohistochemistry of granulocytes and myeloid precursors in the bone marrow showed a large prevalence of COX-1 as compared to COX-2. In conclusion, COX-1 is induced during ATRA-dependent maturation and appears to contribute to myeloid differentiation both in vitro and ex vivo, and COX-1 activity may potentiate the differentiation of human APL.Leukemia (2004) 18, 1373-1379. doi:10.1038/sj.leu.2403407 Published online 10 June 2004


Asunto(s)
Isoenzimas/biosíntesis , Leucemia Promielocítica Aguda/enzimología , Leucemia Promielocítica Aguda/patología , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Regulación hacia Arriba , Células Sanguíneas , Células de la Médula Ósea , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Dinoprostona/biosíntesis , Granulocitos/citología , Humanos , Isoenzimas/análisis , Isoenzimas/genética , Leucemia/enzimología , Leucemia/patología , Proteínas de la Membrana , Mielopoyesis/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/análisis , Prostaglandina-Endoperóxido Sintasas/genética , ARN Mensajero/biosíntesis , Tretinoina/farmacología , Células Tumorales Cultivadas
7.
J Lipid Res ; 45(2): 308-16, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14563831

RESUMEN

Fatty acid synthetase (FAS) is overexpressed in various tumor tissues, and its inhibition and/or malonyl-CoA accumulation have been correlated to apoptosis of tumor cells. It is widely recognized that both omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) depress FAS expression in liver, although epidemiological and experimental reports attribute antitumor properties only to omega-3 PUFA. Therefore, we investigated whether lipogenic gene expression in tumor cells is differently regulated by omega-6 and omega-3 PUFAs. Morris hepatoma 3924A cells were implanted subcutaneously in the hind legs of ACI/T rats preconditioned with high-lipid diets enriched with linoleic acid or alpha-linolenic acid. Both-high lipid diets depressed the expression of FAS and acetyl-CoA carboxylase in tumor tissue, this effect correlating with a decrease in the mRNA level of their common sterol regulatory element binding protein-1 transcription factor. Hepatoma cells grown in rats on either diet did not accumulate malonyl-CoA. Apoptosis of hepatoma cells was induced by the alpha-linolenic acid-enriched diet but not by the linoleic acid-enriched diet. Therefore, in this experimental model, apoptosis is apparently independent of the inhibition of fatty acid synthesis and of malonyl-CoA cytotoxicity. Conversely, it was observed that apoptosis induced by the alpha-linolenic acid-enriched diet correlated with a decrease in arachidonate content in hepatoma cells and decreased cyclooxygenase-2 expression.


Asunto(s)
Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Isoenzimas/genética , Neoplasias Hepáticas Experimentales/patología , Prostaglandina-Endoperóxido Sintasas/genética , Ácido alfa-Linolénico/administración & dosificación , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Animales , Apoptosis/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Ciclooxigenasa 2 , Dieta , Grasas Insaturadas en la Dieta , Regulación hacia Abajo/genética , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Ácidos Grasos Omega-6/genética , Ácidos Grasos Omega-6/metabolismo , Ácidos Grasos Insaturados/genética , Ácidos Grasos Insaturados/metabolismo , Isoenzimas/biosíntesis , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Ratas , Ácido alfa-Linolénico/metabolismo
8.
Chem Res Toxicol ; 16(11): 1440-7, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14615970

RESUMEN

Bezafibrate is a hypolipidemic drug that belongs to the group of peroxisome proliferators because it binds to peroxisome proliferator-activated receptors type alpha (PPARs). Peroxisome proliferators produce a myriad of extraperoxisomal effects, which are not necessarily dependent on their interaction with PPARs. An investigation on the peculiar activities of bezafibrate could clarify some of the molecular events and the relationship with the biochemical and pharmacological properties of this class of compounds. In this view, the human acute promyelocytic leukemia HL-60 cell line and human rabdomiosarcoma TE-671 cell line were cultured in media containing bezafibrate and a number of observations such as spectrophotometric analysis of mitochondrial respiratory chain enzymes, NMR metabolite determinations, phosphofructokinase enzymatic analysis, and differentiation assays were carried on. Bezafibrate induced a derangement of NADH cytochrome c reductase activity accompanied by metabolic alterations, mainly a shift to anaerobic glycolysis and an increase of fatty acid oxidation, as shown by NMR analysis of culture supernatants where acetate, lactate, and alanine levels increased. On the whole, the present results suggest a biochemical profile and a therapeutic role of this class of PPARs ligands more complex than those previously proposed.


Asunto(s)
Bezafibrato/efectos adversos , Enfermedades Mitocondriales/inducido químicamente , Proliferadores de Peroxisomas/efectos adversos , Células Tumorales Cultivadas , Acetatos/química , Acetatos/metabolismo , Alanina/química , Alanina/metabolismo , Animales , Bezafibrato/metabolismo , Bezafibrato/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Hipolipemiantes/efectos adversos , Hipolipemiantes/metabolismo , Hipolipemiantes/farmacología , Italia , Ácido Láctico/química , Ácido Láctico/metabolismo , Espectroscopía de Resonancia Magnética , Microscopía Electrónica , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Proliferadores de Peroxisomas/metabolismo , Proliferadores de Peroxisomas/farmacología , Ratas , Factores de Tiempo
9.
Br J Cancer ; 87(10): 1145-52, 2002 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-12402155

RESUMEN

This study aims at investigating the relationship between cyclooxygenase-2 expression in tumour vs stroma inflammatory compartment and its possible clinical role. The study included 99 stage IB-IV cervical cancer patients: immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase-2. CD3, CD4, CD8, CD25, Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours. An inverse relation was found between cyclooxygenase-2 levels (cyclooxygenase-2 IDV) of tumour vs stroma compartment (r=-0.44, P<0.0001). The percentage of cases showing high tumour/stromal cyclooxygenase-2 IDV ratio was significantly higher in patients who did not respond to treatment (93.3%) with respect to patients with partial (60.5%), and complete (43.7%) response (P= 0.009). Cases with a high tumour/stroma cyclooxygenase-2 IDV ratio had a shorter overall survival rate than cases with a low tumour/stroma cyclooxygenase-2 IDV (P<0.0001). In the multivariate analysis advanced stage and the status of tumour/stroma cyclooxygenase-2 IDV ratio retained an independent negative prognostic role. The proportion of CD3(+), CD4(+), and CD25(+) cells was significantly lower in tumours with high tumour/stroma cyclooxygenase-2 IDV ratio, while a higher percentage of mast cells was detected in tumours showing high tumour/stroma cyclooxygenase-2 IDV ratio. Our study showed the usefulness of assessing cyclooxygenase-2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis.


Asunto(s)
Isoenzimas/análisis , Prostaglandina-Endoperóxido Sintasas/análisis , Neoplasias del Cuello Uterino/enzimología , Adulto , Anciano , Animales , Antígenos CD/análisis , Ciclooxigenasa 2 , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Proteínas de la Membrana , Persona de Mediana Edad , Terapia Neoadyuvante , Conejos , Células del Estroma/enzimología , Análisis de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología
10.
Ann Oncol ; 13(8): 1205-11, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12181243

RESUMEN

BACKGROUND: Cyclooxygenase-2 (COX-2) expression is associated with aggressive clinicopathological parameters and unfavourable prognosis in several human malignancies. The aim of this study was to investigate the expression of COX-2 and its association with clinicopathological parameters, response to treatment, and clinical outcome in ovarian cancer patients. PATIENTS AND METHODS: COX-2 expression was analysed by immunohistochemistry in 87 primary ovarian carcinomas from patients with measurable disease after primary laparotomy. RESULTS: COX-2 immunoreaction was observed in 39 (44.8%) cases, and did not differ in distribution according to age, FIGO stage, debulking at time of surgery, presence of ascites, histotype or tumour grade. Both in patients cytoreduced at first surgery and in those undergoing only explorative laparotomy, the percentage of COX-2 positivity was significantly higher in non-responding than in patients responding to treatment (P = 0.043 and P = 0.0018, respectively). In multivariate analysis, only COX-2 positivity and older age retained an independent role in predicting a poor chance of response to treatment. There was no significant difference of clinical outcome according to COX-2 status in patients undergoing primary debulking while, in the subgroup of patients who underwent explorative laparotomy, COX-2-positive cases showed a shorter time to progression (P = 0.025) and overall survival (P = 0.025). CONCLUSIONS: The assessment of COX-2 status could provide additional information in order to identify ovarian cancer patients with a poor chance of response to chemotherapy and potentially candidates for more individualised treatments.


Asunto(s)
Resistencia a Antineoplásicos , Isoenzimas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Cisplatino/uso terapéutico , Ciclooxigenasa 2 , Progresión de la Enfermedad , Femenino , Humanos , Técnicas para Inmunoenzimas , Proteínas de la Membrana , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/química , Pronóstico , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba
11.
J Clin Oncol ; 20(4): 973-81, 2002 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-11844819

RESUMEN

PURPOSE: To investigate the expression of cyclooxygenase (COX-2) and its association with clinicopathologic parameters and clinical outcome in patients with cervical cancer. PATIENTS AND METHODS: The study included 84 patients with stage IB to IVA cervical cancer. Patients with early-stage cases (n = 21) underwent radical surgery, whereas patients with locally advanced cervical cancer (LACC) (n = 63) were first administered neoadjuvant cisplatin-based treatment and subjected to surgery in case of response. Immunohistochemical analysis was performed on paraffin-embedded sections with rabbit antiserum against COX-2. RESULTS: COX-2--integrated density values in the overall population ranged from 1.2 to 82.3, with mean plus minus SE values of 27.4 plus minus 2.4. According to the chosen cutoff value, 36 (42.9%) of 84 patients were scored as COX-2 positive. COX-2 levels were shown to be highly associated with tumor susceptibility to neoadjuvant treatment. COX-2 showed a progressive increase from mean plus minus SE values of 19.9 plus minus 8.0 in complete responders through 31.5 plus minus 3.5 in partial responses to 44.8 plus minus 3.9 in patients who were not responsive (P =.0054). When logistic regression was applied, only advanced stage and COX-2 positivity retained independent roles in predicting a poor chance of response to treatment. COX-2--positive patients had a shorter overall survival (OS) rate than COX-2--negative patients. In patients with LACC, the 2-year OS rate was 38% in COX-2--positive versus 85% in COX-2--negative patients (P =.0001). In the multivariate analysis, only advanced stage and COX-2 positivity retained independent negative prognostic roles for OS. CONCLUSION: The assessment of COX-2 status could provide additional information to identify patients with cervical cancer with a poor chance of response to neoadjuvant treatment and unfavorable prognosis.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/análisis , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica , Regulación de la Expresión Génica , Isoenzimas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Animales , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Terapia Combinada , Ciclooxigenasa 2 , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunohistoquímica , Proteínas de la Membrana , Persona de Mediana Edad , Terapia Neoadyuvante , Pronóstico , Conejos , Análisis de Supervivencia , Resultado del Tratamiento , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/cirugía
12.
Int J Cancer ; 95(6): 343-9, 2001 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-11668514

RESUMEN

Epidermal growth factor receptor (EGFR) overexpression is an unfavorable prognostic marker in laryngeal squamous cell carcinoma (SCC). EGFR stimulates cyclooxygenase-2 (COX-2) expression in normal human keratinocytes and squamous carcinoma cells. Based on these observations a prognostic role of COX-2 expression in laryngeal SCC can be hypothesized. Consequently, COX-2 expression was studied in laryngeal SCC (median follow-up = 47 months; range: 2-87 months) by quantitative immunohistochemistry (n = 61) and EGFR by binding assay (n = 51). Well-differentiated regions of laryngeal SCC revealed strong COX-2 immunostaining, whereas histologically normal areas neighboring tumor as well as poorly-differentiated tumors were negative. Immunohistochemical results were confirmed by Western blot analyses. Cox's regression analysis showed that the combination of low levels of COX-2 integrated density and high levels of EGFR covariates provided strong prediction, at 5-year follow-up, of both poor overall survival (chi(2) = 12.905; p = 0.0016) and relapse-free survival (chi(2) = 9.209; p = 0.01). In vitro studies on CO-K3 cell line, obtained from an EGFR positive, COX-2 negative poorly-differentiated laryngeal SCC, revealed that EGF stimulation failed to induce COX-2 expression and PGE2 production suggesting a change in EGFR signaling pathway. These findings indicate that COX-2 is overexpressed in less aggressive, low grade laryngeal SCC, whereas its expression is lost when tumors progress to a more malignant phenotype.


Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/enzimología , Isoenzimas/biosíntesis , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/enzimología , Pronóstico , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Anciano , Western Blotting , Diferenciación Celular , Línea Celular , Ciclooxigenasa 2 , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Receptores ErbB/metabolismo , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Queratinocitos/enzimología , Cinética , Proteínas de la Membrana , Persona de Mediana Edad , Análisis Multivariante , Fenotipo , Unión Proteica , Transducción de Señal , Factores de Tiempo , Células Tumorales Cultivadas , Regulación hacia Arriba
13.
Melanoma Res ; 11(5): 469-76, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11595883

RESUMEN

Hyperthermia produces regression of human cancer. Because hyperthermia has produced only limited results, attention has focused on searching for substances able to sensitize tumour cells to the effects of hyperthermia. The flavonoid quercetin has been reported to be a hyperthermic sensitizer in ovarian and uterine cervical tumours and in leukaemia. Quercetin and tamoxifen inhibit melanoma cell growth. We therefore investigated whether quercetin and tamoxifen can sensitize M10, M14 and MNT1 human melanoma cells to hyperthermia. We observed that both quercetin and tamoxifen synergize with hyperthermia (42.5 degrees C) in reducing the clonogenic activity of M14 and MNT1 and in inducing apoptotic cell death in all three cell lines. As revealed by flow cytometric and Northern blot analyses, quercetin and tamoxifen reduced heat shock protein-70 expression at both protein and mRNA levels. Our results suggest that quercetin and tamoxifen can be usefully combined with hyperthermia in the therapy of recurrent and/or metastatic melanoma.


Asunto(s)
Apoptosis/efectos de los fármacos , Hipertermia Inducida , Melanoma/patología , Quercetina/farmacología , Tamoxifeno/farmacología , Northern Blotting , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/biosíntesis , Proteínas HSP70 de Choque Térmico/genética , Calor , Humanos , Etiquetado Corte-Fin in Situ , Melanocitos/efectos de los fármacos , Melanocitos/patología , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Quercetina/uso terapéutico , ARN/genética , ARN/metabolismo , Tamoxifeno/uso terapéutico , Temperatura , Células Tumorales Cultivadas
14.
Clin Cancer Res ; 7(9): 2656-61, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11555576

RESUMEN

PURPOSE: The aim of the study was to investigate if a short-term administration of high-dose Tamoxifen (Tam) could affect the expression of biologically relevant biochemical parameters in cervical cancer tissue. EXPERIMENTAL DESIGN: The study was conducted in 24 patients with histologically confirmed cervical tumors. Biopsies were obtained by colposcopy on day 0 in all patients, who then received either 80 mg/die or 160 mg/die for 5 consecutive days until the second biopsy was obtained. Immunohistochemistry was performed with antiestrogen receptor (ER), anti-Ki67, anticaspase cleavage product of keratin 18 (M30), and anti-CD31 monoclonal antibodies. RESULTS: Eleven (45.8%) of 24 cervical tumors were ER positive. The percentage of Ki67-positive tumor cells in pre-Tam biopsies was significantly higher than the percentage in the corresponding posttreatment biopsies (z = 4.29, P = 0.0001). No difference in the pretreatment percentage of Ki67-positive cells according to ER status was found. The percentage of M30 positivity was higher in post-Tam than in pre-Tam biopsies. Microvessel density values in pre-Tam biopsies were significantly higher than corresponding values in posttreatment tissues (z = -3.72, P = 0.0002). The reduction in the percentage of Ki67-positive tumors was significantly (z = 3.58, P = 0.0003) higher in ER-positive than in ER-negative tumors, whereas no difference in Tam-induced reduction of microvessel density values according to ER status (z = -0.18, P = 0.85) was found. Tam treatment did not induce any change of M30 positivity in ER-positive tumors, whereas in ER-negative tumors, it produced a significant (P = 0.015) increase in the percentage of M30-positive cells in post-Tam versus pre-Tam biopsies. CONCLUSIONS: A short-term treatment with Tam at doses 4-8-fold higher than those in conventional schemes is associated with modifications of biological parameters associated with tumor cell proliferation, apoptosis, and neoangiogenesis in cervical cancer.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Apoptosis/efectos de los fármacos , Vasos Sanguíneos/efectos de los fármacos , Antígeno Ki-67/biosíntesis , Tamoxifeno/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunohistoquímica , Queratinas/análisis , Persona de Mediana Edad , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Receptores de Estrógenos/análisis , Neoplasias del Cuello Uterino/irrigación sanguínea , Neoplasias del Cuello Uterino/patología
15.
J Cell Biochem ; 82(4): 619-33, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11500940

RESUMEN

Angiogenesis, the formation of new capillary blood vessels, occurs almost exclusively in the microcirculation. This process is controlled by the interaction between factors with positive and negative regulatory activity. In this study, we have compared the effect of two well described positive regulators, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) on bovine adrenal cortex-derived microvascular endothelial (BME) and bovine aortic endothelial (BAE) cells. The parameters we assessed included (a) cellular reorganization and lumen formation following exposure of the apical cell surface to a three-dimensional collagen gel; (b) organization of the actin cytoskeleton; (c) expression of thrombospondin-1 (TSP-1), an endogenous negative regulator of angiogenesis; and (d) extracellular proteolytic activity mediated by the plasminogen activator (PA)/plasmin system. We found that (a) collagen gel overlay induces rapid reorganization and lumen formation in BME but not BAE cells; (b) FGF-2 but not VEGF induced dramatic reorganization of actin microfilaments in BME cells, with neither cytokine affecting BAE cells; (c) FGF-2 decreased TSP-1 protein and mRNA expression in BME cells, an effect which was specific for FGF-2 and BME cells, since TSP-1 protein levels were unaffected by VEGF in BME cells, or by FGF-2 or VEGF in BAE cells; (d) FGF-2 induced urokinase-type PA (uPA) in BME and BAE cells, while VEGF induced uPA and tissue-type PA in BME cells with no effect on BAE cells. Taken together, these findings reveal endothelial cell-type specific responses to FGF-2 and VEGF, and point to the greater specificity of these cytokines for endothelial cells of the microvasculature than for large vessel (aortic) endothelial cells. Furthermore, when viewed in the context of our previous observation on the synergistic interaction between VEGF and FGF-2, our present findings provide evidence for complementary mechanisms which, when acting in concert, might account for the synergistic effect.


Asunto(s)
Factores de Crecimiento Endotelial/farmacología , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Linfocinas/farmacología , Neovascularización Fisiológica , Animales , Aorta/citología , Capilares/citología , Bovinos , Tamaño de la Célula/efectos de los fármacos , Células Cultivadas , Colágeno , Citoesqueleto/ultraestructura , Endotelio Vascular/efectos de los fármacos , Adhesiones Focales/ultraestructura , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Inhibidor 1 de Activador Plasminogénico/genética , Activadores Plasminogénicos/biosíntesis , Activadores Plasminogénicos/genética , ARN Mensajero/biosíntesis , Trombospondina 1/biosíntesis , Trombospondina 1/genética , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
16.
Free Radic Biol Med ; 30(9): 1000-7, 2001 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-11316580

RESUMEN

This is the first report demonstrating a relationship between apoptosis induction and changes of intracellular redox potential in the growth-inhibitory effects of high concentrations of beta-carotene in a tumor cell line. beta-Carotene inhibited the growth of human WiDr colon adenocarcinoma cells in a dose- and time-dependent manner, induced apoptosis, and blocked Bcl-2 expression. These effects were accompanied by an enhanced production of intracellular reactive oxygen species (ROS). The addition of the antioxidant alpha-tocopherol blocked both the pro-oxidant and the growth-inhibitory effects of the carotenoid. These findings suggest that beta-carotene may act as an inductor of apoptosis by its pro-oxidant properties.


Asunto(s)
Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , beta Caroteno/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antioxidantes/metabolismo , Antioxidantes/farmacología , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Radicales Libres/metabolismo , Inhibidores de Crecimiento/administración & dosificación , Inhibidores de Crecimiento/farmacología , Humanos , Oxidantes/administración & dosificación , Oxidantes/metabolismo , Oxidantes/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células Tumorales Cultivadas , Vitamina E/metabolismo , Vitamina E/farmacología , Proteína X Asociada a bcl-2 , Proteína bcl-X , beta Caroteno/administración & dosificación , beta Caroteno/metabolismo
17.
Virchows Arch ; 438(2): 159-65, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11253118

RESUMEN

A case of gallbladder involvement by malignant melanoma in a 57-year-old woman is reported. The gallbladder, resected for cholelithiasis, harboured a pedunculated polypoid dark mass, which histologically revealed sheets and nests of epithelioid cells with hyperchromatic nuclei in the lamina propria and at the junctional level. These cells were pigmented (with positive reaction with Schmorl's stain and bleaching with peroxide) and showed immunohistochemical positivity for S-100, gp 100 antigen (HMB-45 antibody) and vimentin. The patient, affected by dysplastic naevus syndrome, had a melanoma in situ excised from the scalp 8 years earlier. The features of the investigated lesion address towards a diagnosis of primary gallbladder melanoma. Furthermore, this is the first time that the existence of such a controversial entity is sustained by the ultrastructural investigation of melanosomes, demonstrating the presence of two melanocitary populations, a typical one exclusively junctional and an atypical one both at the junctional level and in the lamina propria.


Asunto(s)
Síndrome del Nevo Displásico/patología , Neoplasias de la Vesícula Biliar/patología , Melanoma/patología , Supervivencia sin Enfermedad , Femenino , Neoplasias de la Vesícula Biliar/química , Humanos , Inmunohistoquímica , Melanocitos/ultraestructura , Melanoma/química , Melanosomas/ultraestructura , Persona de Mediana Edad , Proteínas S100/análisis , Vimentina/análisis
18.
Blood ; 97(4): 1063-9, 2001 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-11159538

RESUMEN

The receptor for hepatocyte growth factor (HGF) is a transmembrane tyrosine kinase that is encoded by the proto-oncogene c-met. Recently, c-MET was detected in Reed-Sternberg (RS) cells from Epstein-Barr virus-positive (EBV(+)) Hodgkin disease (HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease. In all 45 lymph node and 12 bone marrow samples examined, RS cells expressed c-MET but not HGF(+). These results were independent of the EBV infection. Interestingly, several HGF(+) dendritic-reticulum cells were found scattered around c-MET(+) RS cells. The mean +/- SEM serum HGF levels in HD patients at diagnosis and at the time of relapse were 1403 +/- 91 (95% confidence interval [CI], 1221-1585) and 1497 +/- 242 pg/mL (95% CI, 977-2017), respectively. HGF values were significantly higher than those of healthy individuals (665 +/- 28 pg/mL; 95% CI, 600-721; and P <.001 for both groups of patients) and of HD patients in remission (616 +/- 49 pg/mL; 95% CI, 517-714; and P <.001 for both groups of patients). A significant correlation was found between serum HGF levels and B symptoms at diagnosis (P =.014). In conclusion, this study indicates that HGF and c-MET constitute an additional signaling pathway between RS cells and the reactive cellular background, thereby affecting adhesion, proliferation, and survival of RS cells. Furthermore, the serum concentration of HGF in HD patients may be a useful tool in monitoring the status of disease.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Factor de Crecimiento de Hepatocito/biosíntesis , Enfermedad de Hodgkin/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas Proto-Oncogénicas c-met/biosíntesis , Proto-Oncogenes , Adolescente , Adulto , Anciano , Biopsia , Médula Ósea/patología , Adhesión Celular , División Celular , Células Dendríticas/metabolismo , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Estudios de Seguimiento , Factor de Crecimiento de Hepatocito/sangre , Factor de Crecimiento de Hepatocito/genética , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/genética , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-met/genética , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Transducción de Señal
19.
J Neurooncol ; 49(1): 9-17, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11131990

RESUMEN

One objection to using cell cultures for studying the proliferation of tumors is the potential for phenotypic changes that may occur in vitro. Here, we compared the antigen pattern expression of cultured meningioma cells with that of the primary tumor. Cell cultures established from 9 intracranial meningiomas and deparaffinized sections of the resected tumors were analyzed for immunophenotyping with the following antibodies: vimentin, cytokeratin, epithelial membrane antigen, S-100, neuron-specific enolase, synaptophisin, factor VIII-related antigen, CD4, CD31, CD34, CD45RB, CD68-PGM1, CD68-KP, and myeloid/histiocyte antigen (MAC387). Overall, the cultured meningioma cells retained the main feature of the primary tumor, being positive both for mesenchymal antigens and for epithelial antigens. Interestingly, the cultured meningioma cells abundantly expressed the CD68 antigens at early passage. The CD68 antigens, which are normally found on hematopoietic cells like macrophages and monocytes, were not detectable on meningioma cells in situ. Our results show that phenotypic changes on human meningioma cells may occur in vitro. This phenomenon suggests caution when transposing the in vitro results to the in vivo condition.


Asunto(s)
Neoplasias Meníngeas/genética , Meningioma/genética , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Western Blotting , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patología , Meningioma/metabolismo , Meningioma/patología , Persona de Mediana Edad , Fenotipo , Coloración y Etiquetado , Células Tumorales Cultivadas
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