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1.
Br J Cancer ; 128(8): 1503-1513, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36759720

RESUMO

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Carboplatina , Trabectedina , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/etiologia , Platina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Doxorrubicina , Polietilenoglicóis , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
2.
Gynecol Oncol ; 148(1): 79-85, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29157627

RESUMO

OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. RESULTS: ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p=0.035; RFS: IC50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab (p=0.026). CONCLUSIONS: Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Nitrilas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Triazóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Receptor alfa de Estrogênio/biossíntese , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Imuno-Histoquímica , Letrozol , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adulto Jovem
4.
Br J Cancer ; 111(8): 1634-45, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25167227

RESUMO

BACKGROUND: The level of plasma-derived naturally circulating anti-glycan antibodies (AGA) to P1 trisaccharide has previously been shown to significantly discriminate between ovarian cancer patients and healthy women. Here we aim to identify the Ig class that causes this discrimination, to identify on cancer cells the corresponding P1 antigen recognised by circulating anti-P1 antibodies and to shed light into the possible function of this glycosphingolipid. METHODS: An independent Australian cohort was assessed for the presence of anti-P1 IgG and IgM class antibodies using suspension array. Monoclonal and human derived anti-glycan antibodies were verified using three independent glycan-based immunoassays and flow cytometry-based inhibition assay. The P1 antigen was detected by LC-MS/MS and flow cytometry. FACS-sorted cell lines were studied on the cellular migration by colorimetric assay and real-time measurement using xCELLigence system. RESULTS: Here we show in a second independent cohort (n=155) that the discrimination of cancer patients is mediated by the IgM class of anti-P1 antibodies (P=0.0002). The presence of corresponding antigen P1 and structurally related epitopes in fresh tissue specimens and cultured cancer cells is demonstrated. We further link the antibody and antigen (P1) by showing that human naturally circulating and affinity-purified anti-P1 IgM isolated from patients ascites can bind to naturally expressed P1 on the cell surface of ovarian cancer cells. Cell-sorted IGROV1 was used to obtain two study subpopulations (P1-high, 66.1%; and P1-low, 33.3%) and observed that cells expressing high P1-levels migrate significantly faster than those with low P1-levels. CONCLUSIONS: This is the first report showing that P1 antigen, known to be expressed on erythrocytes only, is also present on ovarian cancer cells. This suggests that P1 is a novel tumour-associated carbohydrate antigen recognised by the immune system in patients and may have a role in cell migration. The clinical value of our data may be both diagnostic and prognostic; patients with low anti-P1 IgM antibodies present with a more aggressive phenotype and earlier relapse.


Assuntos
Antígenos de Neoplasias/imunologia , Glicoesfingolipídeos/imunologia , Metástase Neoplásica/imunologia , Neoplasias Ovarianas/imunologia , Anticorpos Antineoplásicos/imunologia , Anticorpos Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Cromatografia de Afinidade , Feminino , Citometria de Fluxo , Humanos , Neoplasias Ovarianas/patologia
5.
Gynecol Oncol ; 134(2): 338-45, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24924122

RESUMO

OBJECTIVE: Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting ß-catenin dependent and independent Wnt signalling pathways. METHOD: Wnt5a expression was investigated in a large cohort of epithelial ovarian cancer patient samples using immunohistochemistry and correlated with clinicopathological variables. Wnt5a function was investigated in vitro in ovarian cell lines. RESULTS: Wnt5a expression was found to be upregulated in all major subtypes (serous, endometrioid, clear cell and mucinous) of epithelial ovarian cancer compared to borderline tumours and benign controls. Treatment of ovarian surface epithelial cells with recombinant Wnt5a decreased cell adhesion and was associated with increased epithelial to mesenchymal transition (EMT). In addition, downstream targets of ß-catenin dependent Wnt signalling were inhibited, and ß-catenin independent targets increased following Wnt5a upregulation. Knockdown of Wnt5a in ovarian cancer cells was associated with a mesenchymal to epithelial transition (MET), but had no significant effect on cell migration or proliferation. CONCLUSION: This study adds to the increasing evidence that Wnt signalling may play an important role in ovarian cancer development. Utilising an unparalleled large cohort of 623 patients, Wnt5a protein expression was shown to be significantly higher in ovarian cancer patients when compared to benign and borderline ovarian tumours and healthy control patients. In addition, we have utilised in vitro models to show for the first time in ovarian cancer that Wnt5a driven non-canonical pathways can alter epithelial to mesenchymal transition (EMT).


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Epiteliais e Glandulares/etiologia , Neoplasias Ovarianas/etiologia , Proteínas Proto-Oncogênicas/biossíntese , Regulação para Cima , Proteínas Wnt/biossíntese , Carcinoma Epitelial do Ovário , Feminino , Humanos , Transdução de Sinais , Células Tumorais Cultivadas , Proteína Wnt-5a
6.
Pharmacopsychiatry ; 47(1): 29-32, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24307207

RESUMO

The trial was a double-blind, placebo-controlled comparison with a discontinuation design. 49 mentally retarded patients with aggressive behaviour were treated with zuclopenthixol at a dose of 2-20 mg/d. At each visit the clinical effect was evaluated. Correlations between dose, serum concentration, and efficacy measures were calculated. The mean dose was 10.0 mg/day (±5.17); the mean serum concentration 4.19 ng/mL (±3.16). Associations of dosage, serum concentration and clinical efficiency did not result in coherent patterns. Correlations with clinical efficiency measures appeared to be contradictory for dosage and serum concentrations, respectively. As no consistent associations between dosage, serum concentration, and clinical efficiency measures were found, different hypotheses explaining the results are discussed.


Assuntos
Agressão/efeitos dos fármacos , Clopentixol/farmacologia , Clopentixol/uso terapêutico , Monitoramento de Medicamentos , Deficiência Intelectual/tratamento farmacológico , Adolescente , Adulto , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estatística como Assunto , Resultado do Tratamento , Adulto Jovem
7.
Ann Oncol ; 25(2): 322-31, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24285017

RESUMO

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM×anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Murinos , Ensaios Clínicos como Assunto , Daclizumabe , Toxina Diftérica/uso terapêutico , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Imunoterapia , Interleucina-2/uso terapêutico , Ipilimumab , Proteínas Recombinantes de Fusão/uso terapêutico
9.
Patol Fiziol Eksp Ter ; (1): 40-7, 2010.
Artigo em Russo | MEDLINE | ID: mdl-20731126

RESUMO

The review describes physiological and pathological role of interleukin-6 (IL-6) in control of tissues insulin sensitivity and its contrary shifts in different tissues. Analysis of actual data for IL-6 sources and its molecular mechanisms of action is given.


Assuntos
Resistência à Insulina , Interleucina-6/metabolismo , Animais , Humanos
10.
Ter Arkh ; 81(10): 74-80, 2009.
Artigo em Russo | MEDLINE | ID: mdl-19947447

RESUMO

Insulin resistance (IR) is a leading factor of type 2 diabetes (T2D), the central and governing component of the metabolic syndrome (MS), that also appears as obesity, glucose intolerance, dyslipidemia, and essential hypertension. Recent experimental studies have indicated that proinflammatory cytokines, adipocytokines, and transcription factors are implicated in the pathogenesis of IR, as evidenced by a number of clinical observations in patients with MS and T2D, in whom IR correlates with the status of chronic mild inflammation. Based on the results of these studies, a search for methods for exposure of IR has been initiated, by controlling inflammation. The first results encourage and suggest that anti-inflammatory agents improve tissue susceptibility to insulin and they are promising for the treatment of MS and T2D.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Glicemia/análise , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Hemoglobinas Glicadas , Índice Glicêmico , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Inflamação , Resistência à Insulina , Síndrome Metabólica , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Fatores de Risco , Fatores de Tempo
11.
Patol Fiziol Eksp Ter ; (3): 34-8, 2009.
Artigo em Russo | MEDLINE | ID: mdl-19916323

RESUMO

The review presents the currently available data on the role of adipokines, adinonectin in particular, in the regulation of metabolic processes. The pathological role of adinonectin receptors in insulin resistance, diabetes mellitus, metabolic syndrome, atherosclerosis, and other cardiovascular diseases is discussed in detail.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus/metabolismo , Resistência à Insulina , Síndrome Metabólica/metabolismo , Receptores de Adiponectina/metabolismo , Adiponectina/metabolismo , Animais , Humanos
12.
Mol Gen Mikrobiol Virusol ; (2): 28-32, 2009.
Artigo em Russo | MEDLINE | ID: mdl-19517808

RESUMO

The glycosyl hydrolase genes cel5A and xyl3A previously isolated by ourselves within a fragment of DNA from the methagenomic library of cow rumen microflora DNA were sub-cloned and expressed in E. coli. The recombinant proteins Cel5A and Xyl3A were purified and characterized. Cellulase Cel5A belongs to the Family 5 glycosyl hydrolases and is a one-module 38.2 kDa enzyme that hydrolyses the 1,4-glycoside bonds of soluble cellulose substrates and amorphous cellulose, showing its maximal activity (31200 u/mg) on lichenan, a soluble substrate with mixed (beta-1,3-1,4) bonds. The end product of the amorphous cellulose hydrolysis is cellobiose. Cel5A is inactive toward the crystal forms of cellulose. Cel5A is an endoglucanase capable of exohydrolysis. The molecular mass of beta-xylosidase Xyl3A belonging to the Family 3 glycosyl hydrolases is 83.7 kDa. The enzyme is active only on xylooligosaccharides, with the maximal activity shown on xylobiose, the end product of the reaction being xylose. No activity on xylane was hitherto observed. Recombinant Cel5A and Xyl3A are stable over a wide range of pH and temperatures, their maximal activity being observed at pH 6.5 and at 55 degrees C.


Assuntos
Celulase/biossíntese , Celulase/química , Endo-1,4-beta-Xilanases/biossíntese , Endo-1,4-beta-Xilanases/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Rúmen/enzimologia , Animais , Bovinos , Celulase/genética , Celulose/química , Celulose/metabolismo , Clonagem Molecular , Dissacarídeos/química , Dissacarídeos/metabolismo , Endo-1,4-beta-Xilanases/genética , Estabilidade Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Concentração de Íons de Hidrogênio , Hidrólise , Peso Molecular , Engenharia de Proteínas , Proteínas Recombinantes/genética , Temperatura
13.
Rev Med Suisse ; 5(202): 1027-31, 2009 May 06.
Artigo em Francês | MEDLINE | ID: mdl-19530535

RESUMO

The advent of antiretroviral therapies represent a major therapeutic progress which dramatically modifies HIV seropositive people's life during the past fifteen years. After the violence of a formerly rapidly fatal disease comes nowadays the heaviness of a chronic disease. If some problems are new for the patients, it also represents new challenges for the caregivers. Due to the lack of access to medications in certain context or because of nonadherence to treatment, the full potential of these therapies is difficult to reach. We present here the experience of a therapeutic patient educational program for HIV seropositive persons. This program aimed not only to develop patient's skills to elicit them to find a balance between their life and their disease, but also to improve the skills of the caregivers to face the problem of chronicity.


Assuntos
Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Educação de Pacientes como Assunto , Comportamento de Escolha , Cultura , Humanos , Comportamento Social
14.
Br J Cancer ; 98(6): 1085-93, 2008 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-18349819

RESUMO

Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Prognóstico , Estudos Retrospectivos
15.
Phys Rev Lett ; 98(6): 065002, 2007 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-17358952

RESUMO

We present the first collective x-ray scattering measurements of plasmons in solid-density plasmas. The forward scattering spectra of a laser-produced narrow-band x-ray line from isochorically heated beryllium show that the plasmon frequency is a sensitive measure of the electron density. Dynamic structure calculations that include collisions and detailed balance match the measured plasmon spectrum indicating that this technique will enable new applications to determine the equation of state and compressibility of dense matter.

16.
Br J Cancer ; 94(6): 904-13, 2006 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-16508639

RESUMO

Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT-PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.


Assuntos
Adenocarcinoma Mucinoso/genética , Perfilação da Expressão Gênica , Marcadores Genéticos , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/patologia , Transformação Celular Neoplásica , Progressão da Doença , Feminino , Galectina 4/biossíntese , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/patologia , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Phys Chem Chem Phys ; 7(9): 1990-5, 2005 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-19787904

RESUMO

The equation of state of the noble gases helium, argon, and xenon as well as of hydrogen and deuterium is determined by considering reactions such as dissociation and ionization within a chemical picture. The molecular and atomic constituents, i.e., the neutral particles, are treated within fluid variational theory, while for the charged particles a plasma model is applied. Results are given for densities and temperatures relevant to the interior of giant planets. Comparison is performed with available shock-wave experiments and other theoretical work.


Assuntos
Físico-Química/métodos , Hélio/química , Hidrogênio/química , Gases Nobres/química , Algoritmos , Deutério/química , Modelos Estatísticos , Pressão , Trítio/química
18.
Ann Oncol ; 14(6): 938-45, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12796033

RESUMO

BACKGROUND: Ataxia-telangiectasia is a pleiotropic autosomal recessive disorder caused by mutations in the ATM gene. In addition to a profound cancer predisposition, another hallmark of ataxia-telangiectasia is radiosensitivity. Recently, p53-null mouse fibroblasts have been reported to be radiosensitised by the concurrent loss of ATM. MATERIALS AND METHODS: We compared the sensitivity of atm(+/+)/p53(-/-) and atm(-/-)/p53(-/-) mouse embryonic fibroblasts to different classes of chemotherapeutic agents using the MTT assay, Trypan Blue exclusion and fluorescence-activated cell sorting for cell cycle and apoptosis analyses. RESULTS: Loss of ATM function in p53-deficient cells resulted in a 2- to 4-fold increase in sensitivity to the topoisomerase I poisons camptothecin and topotecan, to the topoisomerase II poisons doxorubicin, epirubicin and etoposide, and to the antimetabolites 5-fluorouracil and gemcitabine, but not to the platinum compounds cisplatin, carboplatin and oxaliplatin, the taxanes docetaxel and paclitaxel, or to busulfan. Loss of ATM function did not result in increased apoptosis, but resulted in increased Trypan Blue staining in response to epirubicin, suggesting that processes other than apoptosis may mediate cytotoxicity. ATM deficiency did not alter the extent of G(1)/S or G(2)/M cell cycle phase accumulation produced by epirubicin, suggesting that enhanced sensitivity was not due to failure of checkpoint activation. CONCLUSIONS: We provide further evidence that ATM is involved in regulating cellular defences against some cytotoxic agents in the absence of p53. Tumour-targeted functional inhibition of ATM may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers.


Assuntos
Antineoplásicos/toxicidade , Fibroblastos/efeitos dos fármacos , Deleção de Genes , Proteínas Serina-Treonina Quinases/fisiologia , Inibidores da Topoisomerase II , Proteína Supressora de Tumor p53/deficiência , Animais , Antimetabólitos/toxicidade , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/toxicidade , Fibroblastos/metabolismo , Homozigoto , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Azul Tripano , Proteínas Supressoras de Tumor
19.
Br J Cancer ; 87(9): 1027-33, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12434296

RESUMO

A large fraction of human tumours carries mutations in the p53 gene. p53 plays a central role in controlling cell cycle checkpoint regulation, DNA repair, transcription, and apoptosis upon genotoxic stress. Lack of p53 function impairs these cellular processes, and this may be the basis of resistance to chemotherapeutic regimens. By virtue of the involvement of DNA mismatch repair in modulating cytotoxic pathways in response to DNA damaging agents, we investigated the effects of loss of Pms2 on the sensitivity to a panel of widely used anticancer agents in E1A/Ha-Ras-transformed p53-null mouse fibroblasts either proficient or deficient in Pms2. We report that lack of the Pms2 gene is associated with an increased sensitivity, ranging from 2-6-fold, to some types of anticancer agents including the topoisomerase II poisons doxorubicin, etoposide and mitoxantrone, the platinum compounds cisplatin and oxaliplatin, the taxanes docetaxel and paclitaxel, and the antimetabolite gemcitabine. In contrast, no change in sensitivity was found after treatment with 5-fluorouracil. Cell cycle analysis revealed that both, Pms2-deficient and -proficient cells, retain the ability to arrest at the G2/M upon cisplatin treatment. The data indicate that the concomitant loss of Pms2 function chemosensitises p53-deficient cells to some types of anticancer agents, that Pms2 positively modulates cell survival by mechanisms independent of p53, and that increased cytotoxicity is paralleled by increased apoptosis. Tumour-targeted functional inhibition of Pms2 may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers.


Assuntos
Adenosina Trifosfatases/fisiologia , Antineoplásicos/farmacologia , Linhagem Celular Transformada/efeitos dos fármacos , Enzimas Reparadoras do DNA , Proteínas de Ligação a DNA/fisiologia , Fibroblastos/efeitos dos fármacos , Taxoides , Proteína Supressora de Tumor p53/deficiência , Animais , Apoptose/efeitos dos fármacos , Pareamento Incorreto de Bases , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Transformada/metabolismo , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fluoruracila/farmacologia , Homozigoto , Camundongos , Camundongos Knockout , Endonuclease PMS2 de Reparo de Erro de Pareamento , Compostos Organoplatínicos/farmacologia , Azul Tripano
20.
Br J Cancer ; 86(7): 1130-5, 2002 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-11953861

RESUMO

Loss of DNA mismatch repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumours. DNA mismatch repair-deficient cells have been reported to be resistant to many chemotherapeutic agents and to radiotherapy, and to have the potential of rapidly acquiring additional mutations leading to tumour progression. Photodynamic therapy is a new treatment modality using light to activate a photosensitiser that preferentially localises in tumour cells. An oxygen dependent photochemical reaction ensues, resulting in selective tumour necrosis. The effect of loss of DNA mismatch repair activity on the sensitivity to photodynamic therapy was tested using pairs of cell lines proficient or deficient in mismatch repair due to loss of either MLH1 or MSH2 protein function. Cells were incubated with the photosensitiser 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin and exposed to laser light at 652 nm with various optical doses ranging from 0-1 J cm(-2). Cell survival was assessed using the clonogenic assay. Loss of MLH1 or MSH2 function was not associated with resistance to photodynamic therapy. MCF-7 cells repeatedly treated with photodynamic therapy expressed parental levels of MLH1, MSH2, MSH6, and PMS2. DNA mismatch repair-deficient and -proficient cells showed similar subcellular distributions of meta-tetra(hydroxyphenyl)chlorin as analysed by laser scanning and fluorescence microscopy. Therefore, repeated exposure of tumour cells to photodynamic therapy does not seem to result in loss of DNA mismatch repair, and loss of mismatch repair, in turn, does not seem to contribute to resistance to photodynamic therapy. Our results suggest recommending photodynamic therapy as a strategy for circumventing resistance due to loss of DNA mismatch repair.


Assuntos
Pareamento Incorreto de Bases , Reparo do DNA , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias/genética , Fotoquimioterapia , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Proteínas de Transporte , Neoplasias Colorretais/patologia , Humanos , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/biossíntese , Proteínas Nucleares , Proteínas Proto-Oncogênicas/biossíntese , Células Tumorais Cultivadas
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