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1.
Eur Rev Med Pharmacol Sci ; 14(5): 471-5, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20556927

RESUMO

INTRODUCTION: The aim of this study was to investigate the presence and the role of the parathyroid hormone-related protein (PTH-rP) in the inflamed pulp. MATERIALS AND METHODS: Thirty-four pulp tissue specimens (24 inflamed and 10 normal pulps) from extracted third molars were studied. The presence of PTH-rP was observed by using immunohistochemistry. Negative controls were performed using non immunized rabbit or mouse serum, omitting the primary antibody. RESULTS: The analysis of all the sections of normal pulps showed the presence of PTHrP positive cells only in the odontoblastic zone and in few fibroblasts. Instead all inflamed pulps showed PTHrP positive cells both in vascular zone and in pulp stroma, as well as in the odontoblastic and subodontoblastic zone. CONCLUSION: Several works proved that this peptide plays a role even in angiogenesis process, but its function is controversial. It is possible to hypothesize that PTHrP stimulates angiogenesis, but it is recommended to further conduct research on this area.


Assuntos
Polpa Dentária/patologia , Inflamação/patologia , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Adulto , Animais , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Neovascularização Fisiológica/fisiologia , Odontoblastos/metabolismo , Coelhos , Adulto Jovem
2.
Carcinogenesis ; 27(12): 2383-91, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16704989

RESUMO

Results from some intervention trials indicated that supplemental beta-carotene enhanced lung cancer incidence and mortality in chronic smokers. The aim of this study was to verify the hypothesis that high concentrations of the carotenoid, under the pO2 present in lung (100-150 mmHg), may exert deleterious effects through a prooxidant mechanism. To test this hypothesis, we examined the interactions of beta-carotene and cigarette smoke condensate (tar) on the formation of lipid peroxidation products in rat lung microsomal membranes enriched in vitro with varying beta-carotene concentrations (from 1 to 10 nmol/mg prot) and then incubated with tar (6-25 microg/ml) under different pO2. As markers of lipid peroxidation, we evaluated the levels of conjugated dienes and malondialdehyde, possessing mutagenic and pro-carcinogenic activity. The exposure of microsomal membranes to tar induced a dose-dependent enhancement of lipid peroxidation, which progressively increased as a function of pO2. Under a low pO2 (15 mmHg), beta-carotene acted clearly as an antioxidant, inhibiting tar-induced lipid peroxidation. However, the carotenoid progressively lost its antioxidant efficiency by increasing pO2 (50-100 mmHg) and acted as a prooxidant at pO2 ranging from 100 to 760 mmHg in a dose-dependent manner. Consistent with this finding, the addition of alpha-tocopherol (25 microM) prevented the prooxidant effects of the carotenoid. beta-Carotene auto-oxidation, measured as formation of 5,6-epoxy-beta,beta-carotene, was faster at high than at low pO2 and the carotenoid was more rapidly consumed in the presence of tar. These data point out that the carotenoid may enhance cigarette smoke-induced oxidative stress and exert potential deleterious effects at the pO2 normally present in lung tissue.


Assuntos
Peróxidos Lipídicos/metabolismo , Neoplasias Pulmonares/epidemiologia , Pulmão/fisiologia , Consumo de Oxigênio , Fumaça/efeitos adversos , beta Caroteno/farmacologia , Humanos , Pulmão/efeitos dos fármacos , Neoplasias Pulmonares/induzido quimicamente , Malondialdeído/metabolismo , Microssomos/efeitos dos fármacos , Microssomos/fisiologia , Mutagênicos , Oxigênio/farmacologia , Fumar , alfa-Tocoferol/farmacologia , beta Caroteno/toxicidade
3.
Apoptosis ; 10(6): 1445-56, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16215689

RESUMO

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.


Assuntos
Apoptose/efeitos dos fármacos , Carotenoides/farmacologia , Ciclina D1/metabolismo , Fibroblastos/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fumaça/efeitos adversos , Proteína de Morte Celular Associada a bcl/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Animais , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Licopeno , Fosfoproteínas/metabolismo , Ratos , Fumar/efeitos adversos , Nicotiana , Proteína Supressora de Tumor p53/metabolismo
4.
Phytother Res ; 19(2): 152-7, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15852493

RESUMO

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.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Ferula , Fitoterapia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Humanos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico
5.
Neurology ; 64(3): 536-8, 2005 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-15699390

RESUMO

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.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Miastenia Gravis/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Timo/patologia , Adolescente , Adulto , Especificidade de Anticorpos , Atrofia , Criança , Feminino , Humanos , Hiperplasia , Subpopulações de Linfócitos/imunologia , Masculino , Miastenia Gravis/classificação , Miastenia Gravis/patologia , Miastenia Gravis/cirurgia , Método Simples-Cego , Timectomia , Timo/imunologia , Timo/cirurgia
6.
Br J Cancer ; 92(2): 271-7, 2005 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-15655541

RESUMO

We investigated the association of survivin expression with prognosis and other apoptosis-related biological factors in 110 primary ovarian cancer patients admitted to the Division of Gynecologic Oncology, Catholic University of Rome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections by using polyclonal antibody ab469 for survivin, and mouse monoclonal antibodies (clone 124 and DO-7), for bcl-2 and p53, respectively. Cytoplasmic survivin immunoreaction was observed in 84.5% cases, while nuclear survivin immunostaining was observed in 29.1% cases. We failed to find any relationship between cytoplasmic survivin positivity rate and any of the parameters examined. Serous tumours showed a lower percentage of nuclear survivin positivity with respect to other histotypes (20.5 vs 48.6%, respectively; P-value=0.004). The percentage of nuclear survivin positivity was higher in cases subjected to primary tumour cytoreduction (43.5%), with respect to patients subjected to exploratory laparotomy (20%) (P=0.024). Bcl-2 and p53 were, respectively, expressed in 27.3 and 60.0% of the cases and their expression was not correlated with survivin status. During the follow-up period, progression and death of disease were observed in 68 (61.8%) and 53 (48.2%) cases, respectively. There was no difference in time to progression and overall survival according to survivin status in ovarian cancer patients. In conclusion, in our experience, the immunohistochemical assessment of survivin status does not seem to be helpful in the prognostic characterisation of ovarian cancer. A more in depth investigation of the complex physiology of divergent survivin variants is needed in order to clarify the biological and the clinical role of differentially located survivin isoforms.


Assuntos
Apoptose/fisiologia , Biomarcadores Tumorais/análise , Proteínas Associadas aos Microtúbulos/biossíntese , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose , Proteínas de Neoplasias , Neoplasias Ovarianas/mortalidade , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Análise de Sobrevida , Survivina , Proteína Supressora de Tumor p53/biossíntese
7.
Leukemia ; 18(8): 1373-9, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15190260

RESUMO

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


Assuntos
Isoenzimas/biossíntese , Leucemia Promielocítica Aguda/enzimologia , Leucemia Promielocítica Aguda/patologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Regulação para Cima , Células Sanguíneas , Células da Medula Óssea , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Dinoprostona/biossíntese , Granulócitos/citologia , Humanos , Isoenzimas/análise , Isoenzimas/genética , Leucemia/enzimologia , Leucemia/patologia , Proteínas de Membrana , Mielopoese/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/análise , Prostaglandina-Endoperóxido Sintases/genética , RNA Mensageiro/biossíntese , Tretinoína/farmacologia , Células Tumorais Cultivadas
8.
Oncol Res ; 14(2): 83-91, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14649542

RESUMO

Epidermal growth factor receptor (EGFR) plays a role in laryngeal squamous cell carcinoma (SCC) development and progression. The flavonoid quercetin (Q) and the antiestrogen tamoxifen (TAM) inhibit proliferation of both primary laryngeal SCC and laryngeal carcinoma cell lines, through still uncharacterized mechanisms. We studied Q and TAM inhibitory effect on epidermal growth factor (EGF)-stimulated Hep2 and CO-K3 laryngeal squamous cell lines. Q and TAM (0.1-1.0 microM) induced more apoptosis in EGF growth-stimulated than in unstimulated Hep2 cells. EGF neither stimulated CO-K3 cell growth nor enhanced Q and TAM-induced apoptosis. Mitogen-activated protein kinase (MAPK) analysis revealed that in Hep2 cells, but not in CO-K3 cells, EGF induced a time-dependent phosphorylation of p42, p44, p38, and p46. In Hep2 cells, but not in CO-K3 cells, Q and TAM produced, upon EGF treatment, a twofold increase of p38 and p46 and an enhancement of p42 and p44 dephosphorylation, suggesting a requirement of EGFR. The enhancing effect was due to a p38 and p46 dephosphorylation delayed kinetics. An antiphosphorylated p38 antibody prevented Q and TAM inhibitory effect on p42 and p44 phosphorylations, suggesting that the EGF-dependent increase in Q and TAM apoptotic effect on Hep2 cells could depend on the p38 inhibition of the survival kinases p42 and p44. In SCC, EGFR overexpression is an early event from dysplasia to neoplasia. We conclude that the capacity of Q and TAM to increase apoptosis in EGFR-activated cells makes these compounds possible chemopreventive drugs in subjects at risk of developing laryngeal cancer.


Assuntos
Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas , Fator de Crescimento Epidérmico/farmacologia , Neoplasias Laríngeas , Quercetina/farmacologia , Tamoxifeno/farmacologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Receptores ErbB/biossíntese , Humanos , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Fatores de Tempo
9.
Int J Radiat Oncol Biol Phys ; 55(1): 21-7, 2003 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-12504032

RESUMO

PURPOSE: To investigate whether cyclooxygenase-2 (COX-2) could be a marker of clinical outcome in cervical cancer patients undergoing concomitant chemoradiation plus surgery. METHODS AND MATERIALS: The study included 33 locally advanced cervical cancer patients; all underwent neoadjuvant chemoradiation, and responsive patients underwent radical surgery. Immunohistochemistry was performed with rabbit antiserum against COX-2. RESULTS: COX-2 integrated density values (IDVs) in the tumor component ranged from 1.4 to 72.3 (median 15.0); in stromal inflammatory cells, COX-2 IDVs ranged from 1.4 to 96.0 (median 16.0). A statistically significant inverse relation was found between the COX-2 IDVs of the tumor vs. the stromal inflammatory component (r = -0.52, p = 0.0017). When the ratio between COX-2 IDV in the tumor vs. the stromal compartment was 1) tumor/stroma COX-2 IDV ratio. Patients with a high tumor/stroma COX-2 IDV ratio had a shorter disease-free survival than did those with a low tumor/stroma COX-2 IDV ratio (p = 0.030). Similarly, those with a high tumor/stroma COX-2 IDV ratio had a shorter overall survival (p = 0.033). CONCLUSION: The assessment of COX-2 status in both the tumor and the stromal compartment could provide additional information in the prognostic characterization of cervical cancer patients administered concomitant chemoradiation plus surgery.


Assuntos
Isoenzimas/análise , Prostaglandina-Endoperóxido Sintases/análise , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Terapia Combinada , Ciclo-Oxigenase 2 , Feminino , Humanos , Imuno-Histoquímica , Proteínas de Membrana , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/mortalidade
10.
Br J Cancer ; 87(10): 1145-52, 2002 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-12402155

RESUMO

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.


Assuntos
Isoenzimas/análise , Prostaglandina-Endoperóxido Sintases/análise , Neoplasias do Colo do Útero/enzimologia , Adulto , Idoso , Animais , Antígenos CD/análise , Ciclo-Oxigenase 2 , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Proteínas de Membrana , Pessoa de Meia-Idade , Terapia Neoadjuvante , Coelhos , Células Estromais/enzimologia , Análise de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
11.
Ann Oncol ; 13(8): 1205-11, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12181243

RESUMO

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.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Isoenzimas/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Cisplatino/uso terapêutico , Ciclo-Oxigenase 2 , Progressão da Doença , Feminino , Humanos , Técnicas Imunoenzimáticas , Proteínas de Membrana , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/química , Prognóstico , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
12.
Gynecol Oncol ; 85(2): 305-10, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11972392

RESUMO

OBJECTIVES: Cyclooxygenase-2 (COX-2) seems to be involved in critical steps of cancer onset and progression. Abnormalities of epidermal growth factor receptor (EGFR) and Her-2/neu have been actively investigated in ovarian cancer and associated with unfavorable clinical outcome. The involvement of COX-2 in ErbB family pathways has been proposed. We investigated by immunohistochemistry the expression of COX-2, EGFR, and Her-2/neu in a series of advanced primary ovarian cancers. METHODS: The study included 76 consecutive stage IIIC-IV ovarian cancer patients with measurable disease after first surgery. Immunohistochemistry was performed on paraffin-embedded sections with rabbit antiserum against COX-2, murine monoclonal antibody (MoAb) 300G9 against Her-2/neu, and monoclonal antibody 108 against EGFR. RESULTS: No association among COX-2, EGFR, and HER-2/neu was found. COX-2 positivity was found in a statistically significant higher percentage of unresponsive cases (80.0%) than in patients responding to chemotherapy (35.7%) (P = 0.0008). The association between COX-2 positivity and poor chance of response to treatment was retained in multivariate analysis. In the subgroup of patients who underwent explorative laparotomy COX-2-positive cases showed a shorter overall survival (P = 0.049). CONCLUSIONS: COX-2 could represent a possible new marker of sensitivity to platin-based chemotherapy in ovarian cancer. The lack of association of COX-2 with EGFR or Her-2/neu suggests that the ability of COX-2 to predict tumor sensitivity to chemotherapy is not dependent on EGFR or Her-2/neu status and could be independently associated with prognosis. In this context, the availability of agents able to specifically interfere with COX-2, Her-2/neu, or EGFR tyrosine kinase is of potential interest.


Assuntos
Receptores ErbB/biossíntese , Isoenzimas/biossíntese , Neoplasias Ovarianas/metabolismo , Prostaglandina-Endoperóxido Sintases/biossíntese , Receptor ErbB-2/biossíntese , Ciclo-Oxigenase 2 , Feminino , Humanos , Imuno-Histoquímica , Proteínas de Membrana , Estadiamento de Neoplasias , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia
13.
J Clin Oncol ; 20(4): 973-81, 2002 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11844819

RESUMO

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.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica , Regulação da Expressão Gênica , Isoenzimas/biossíntese , Prostaglandina-Endoperóxido Sintases/biossíntese , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Animais , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Ciclo-Oxigenase 2 , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica , Proteínas de Membrana , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Coelhos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/cirurgia
14.
Int J Cancer ; 95(6): 343-9, 2001 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-11668514

RESUMO

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.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/enzimologia , Isoenzimas/biossíntese , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/enzimologia , Prognóstico , Prostaglandina-Endoperóxido Sintases/biossíntese , Idoso , Western Blotting , Diferenciação Celular , Linhagem Celular , Ciclo-Oxigenase 2 , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Seguimentos , Humanos , Imuno-Histoquímica , Queratinócitos/enzimologia , Cinética , Proteínas de Membrana , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Ligação Proteica , Transdução de Sinais , Fatores de Tempo , Células Tumorais Cultivadas , Regulação para Cima
15.
Melanoma Res ; 11(5): 469-76, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11595883

RESUMO

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.


Assuntos
Apoptose/efeitos dos fármacos , Hipertermia Induzida , Melanoma/patologia , Quercetina/farmacologia , Tamoxifeno/farmacologia , Northern Blotting , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico HSP70/genética , Temperatura Alta , Humanos , Marcação In Situ das Extremidades Cortadas , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/terapia , Quercetina/uso terapêutico , RNA/genética , RNA/metabolismo , Tamoxifeno/uso terapêutico , Temperatura , Células Tumorais Cultivadas
16.
Clin Cancer Res ; 7(9): 2656-61, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11555576

RESUMO

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.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Apoptose/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Antígeno Ki-67/biossíntese , Tamoxifeno/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imuno-Histoquímica , Queratinas/análise , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Receptores de Estrogênio/análise , Neoplasias do Colo do Útero/irrigação sanguínea , Neoplasias do Colo do Útero/patologia
17.
J Oral Pathol Med ; 30(5): 305-8, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11334467

RESUMO

The human DNA mismatch repair (hMMR) system plays an important role in reducing mutation and maintaining genomic stability. The MMR system in human cells is composed of at least six genes (hMSH2, hMLH1, hMSH3, hPMS1, hPMS2 and GTBP/hMSH6). In particular, hMSH2 and hMLH1 are expressed in human cells that are undergoing rapid renewal; their reduced expression has been reported in several tumors. We examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in 25 ameloblastomas. All ameloblastomas expressed hMSH2 and hMLH1 proteins in the outer layer of epithelial cells. The localization of the staining was exclusively nuclear. These data suggest that the development and progression of these tumors do not depend on a defect in the hMMR system.


Assuntos
Ameloblastoma/genética , Pareamento Incorreto de Bases , Reparo do DNA/genética , Proteínas de Ligação a DNA , Neoplasias Maxilomandibulares/genética , Proteínas , Proteínas Proto-Oncogênicas/biossíntese , Ameloblastoma/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Maxilomandibulares/metabolismo , Repetições de Microssatélites , Proteína 2 Homóloga a MutS , Biossíntese de Proteínas
18.
Free Radic Biol Med ; 30(9): 1000-7, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11316580

RESUMO

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.


Assuntos
Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , beta Caroteno/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Radicais Livres/metabolismo , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/farmacologia , Humanos , Oxidantes/administração & dosagem , Oxidantes/metabolismo , Oxidantes/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Tumorais Cultivadas , Vitamina E/metabolismo , Vitamina E/farmacologia , Proteína X Associada a bcl-2 , Proteína bcl-X , beta Caroteno/administração & dosagem , beta Caroteno/metabolismo
19.
Cancer Chemother Pharmacol ; 46(4): 305-12, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11052628

RESUMO

PURPOSE: Among flavonoids, chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. We studied a panel of newly developed chalcone analogues (S1-S10) using MDA-MB 231 and MCF-7 ADRr breast cancer cells and the T-leukemic Jurkat cell line. Quercetin was used as the reference compound. METHODS: Antiproliferative activity was evaluated by cell counts performed after 72 h of exposure to the drugs. DNA analysis and redox activity were evaluated using flow cytometry. Apoptosis was assessed by morphological analysis, using YOYO-1 as DNA dye; p-glycoprotein function was ascertained by quantitating the efflux of rhodamine 123. RESULTS: All cells were sensitive to chalcone analogues yielding IC50 in micromolar concentrations with the following order regardless of the multidrug resistance (MDR) status: S1 > S2 > quercetin. S1 and S2, the most active compounds, were selected to evaluate their effect on the cell cycle, apoptosis, redox activity, and modulation of the p-glycoprotein function. No significant perturbation in cell cycle was seen with concentration up to 1 microM after 24 h. After 72 h a slight increase in G2/M block and DNA fragmentation occurred at 10 microM. Morphological analysis of apoptosis showed that chalcone analogues induced apoptosis to a higher extent than quercetin. Redox analysis demonstrated that all substances were able to increase intracellular thiol levels, which returned to baseline value after 24 h for all drugs except quercetin. Production of reactive oxygen species was essentially unaffected by all compounds. Finally, in MDR-positive MCF-7 ADRr cells chalcone analogues were unable to modulate p-glycoprotein function while quercetin was able to. CONCLUSIONS: Newly developed S1 and S2 chalcones have a different but higher antitumor activity than quercetin and could be considered as potential new anticancer drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Chalcona/análogos & derivados , Chalcona/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Fabaceae/química , Genes MDR/genética , Humanos , Células Jurkat/efeitos dos fármacos , Plantas Medicinais , Espécies Reativas de Oxigênio/metabolismo , Rodamina 123 , Células Tumorais Cultivadas
20.
Int J Cancer ; 87(4): 595-600, 2000 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10918203

RESUMO

Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma.


Assuntos
Anticarcinógenos/farmacologia , Flavonoides/farmacologia , Melanoma Experimental/patologia , Quercetina/farmacologia , Animais , Anticarcinógenos/uso terapêutico , Apigenina , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Divisão Celular/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/uso terapêutico , Feminino , Flavonoides/uso terapêutico , Inibidores do Crescimento/farmacologia , Inibidores do Crescimento/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Melanoma Experimental/prevenção & controle , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Transplante de Neoplasias , Quercetina/uso terapêutico , Resveratrol , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Células Tumorais Cultivadas
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