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1.
Respir Res ; 24(1): 15, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639661

RESUMO

BACKGROUND: Chronic respiratory diseases are disorders of the airways and other structures of the lung, and include chronic obstructive pulmonary disease (COPD), lung cancer, asthma, bronchiectasis, interstitial lung diseases, occupational lung diseases and pulmonary hypertension. Through this article we take a broad view of chronic lung disease while highlighting (1) the complex interactions of lung diseases with environmental factors (e.g. climate change, smoking and vaping) and multimorbidity and (2) proposed areas to strengthen for better global patient outcomes. CONCLUSION: We suggest new directions for the research agenda in high-priority populations and those experiencing health disparities. We call for lung disease to be made a research priority with greater funding allocation globally.


Assuntos
Asma , Doenças Pulmonares Intersticiais , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Crônica , Pulmão
2.
Med J Aust ; 217(1): 36-42, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35780458

RESUMO

BACKGROUND: About 44% of Indigenous Australian women smoke during pregnancy, compared with 12% of pregnant non-Indigenous women. Health care providers can assist smoking cessation, but they are not typically trained in culturally appropriate methods. OBJECTIVES: To determine whether a health care worker training intervention increases smoking cessation rates among Indigenous pregnant smokers compared with usual care. METHODS AND ANALYSIS: Supporting Indigenous Smokers to Assist Quitting (SISTAQUIT) study is a multicentre, hybrid type 1, pragmatic, cluster randomised controlled trial that compares the effects of an intervention for improving smoking cessation by pregnant Indigenous women (16 years or older, 32 weeks' gestation or less) with usual care. Twenty-one health services caring for Indigenous people in five Australian jurisdictions were randomised to the intervention (ten sites) or control groups (eleven sites). Health care providers at intervention sites received smoking cessation care training based on the ABCD (ask/assess; brief advice; cessation; discuss psychosocial context) approach to smoking cessation for Indigenous women, an educational resource package, free oral nicotine replacement therapy for participating women, implementation support, and trial implementation training. Health care providers in control group services provided usual care. PRIMARY OUTCOME: abstinence from smoking (self-reported abstinence via survey, validated by carbon monoxide breath testing when possible) four weeks after enrolment in the study. SECONDARY OUTCOMES: health service process evaluations; knowledge, attitudes, and practices of health care providers; and longer term abstinence, perinatal outcomes, and respiratory outcomes for babies (to six months). Ethics approval: The human research ethics committees of the University of Newcastle (H-2015-0438) and the Aboriginal Health and Medical Research Council of NSW (1140/15) provided the primary ethics approval. Dissemination of results: Findings will be disseminated in peer-reviewed publications, at local and overseas conferences, and via public and social media, and to participating health services in art-based formats and reports. Policy briefs will be communicated to relevant government organisations. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12618000972224 (prospective).


Assuntos
Serviços de Saúde do Indígena , Abandono do Hábito de Fumar , Austrália , Feminino , Pessoal de Saúde , Humanos , Povos Indígenas , Havaiano Nativo ou Outro Ilhéu do Pacífico , Gravidez , Estudos Prospectivos , Fumar/psicologia , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco
3.
Artigo em Inglês | MEDLINE | ID: mdl-29258185

RESUMO

Clinicians often ask pregnant women about tobacco smoking, but their practices of asking about other smoking and nicotine exposures are unknown. This study analysed how often clinicians ask pregnant women about their use of e-cigarettes, cannabis, chewing tobacco, and second-hand smoke (SHS) exposure. Two cross-sectional surveys were undertaken. A random sample of 500 General Practitioner (GP) members were invited from the National Faculty of Aboriginal and Torres Strait Islander Health (NFATSIH) to complete an on-line survey, and 5571 GP and Obstetrician (OBS) members of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) were sent a paper survey by mail. Questions on frequency of asking about the exposures used Likert Scales, later dichotomized to "often-always" and "never-sometimes". Logistic regressions estimated associations between clinician type and asking about cannabis, e-cigarettes, chewing tobacco, and SHS. An adjusted model reduced potential confounders of location, guidelines, gender and population. n = 378 GPs and OBS participated (6.2% response). In total, 13-14% asked "often-always" about e-cigarettes; 58% cannabis; 38% cannabis with tobacco; 27% SHS, and 10% chewing tobacco-compared to 95% of the sample asking about cigarette smoking. After adjustment, the odds of RANZCOG GPs (OR 0.34) and OBS (OR 0.63) asking about cannabis were lower compared to NFATSIH GPs. Clinician type was non-significant for asking about e-cigarettes, chewing tobacco and SHS. Surveyed Australian GPs and obstetricians asked less frequently about e-cigarettes, chewing, SHS exposure, and cannabis, potentially missing important exposures for mother and child.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Fumar Maconha/epidemiologia , Prevenção do Hábito de Fumar/estatística & dados numéricos , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Adulto , Austrália/epidemiologia , Cannabis , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Gravidez , Fumar/epidemiologia , Inquéritos e Questionários , Nicotiana , Tabaco sem Fumaça
4.
Implement Sci ; 12(1): 114, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28915815

RESUMO

BACKGROUND: Indigenous smoking rates are up to 80% among pregnant women: prevalence among pregnant Australian Indigenous women was 45% in 2014, contributing significantly to the health gap for Indigenous Australians. We aimed to develop an implementation intervention to improve smoking cessation care (SCC) for pregnant Indigenous smokers, an outcome to be achieved by training health providers at Aboriginal Medical Services (AMS) in a culturally competent approach, developed collaboratively with AMS. METHOD: The Behaviour Change Wheel (BCW), incorporating the COM-B model (capability, opportunity and motivation for behavioural interventions), provided a framework for the development of the Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy implementation intervention at provider and patient levels. We identified evidence-practice gaps through (i) systematic literature reviews, (ii) a national survey of clinicians and (iii) a qualitative study of smoking and quitting with Aboriginal mothers. We followed the three stages recommended in Michie et al.'s "Behaviour Change Wheel" guide. RESULTS: Targets identified for health provider behaviour change included the following: capability (psychological capability, knowledge and skills) by training clinicians in pharmacotherapy to assist women to quit; motivation (optimism) by presenting evidence of effectiveness, and positive testimonials from patients and clinicians; and opportunity (environmental context and resources) by promoting a whole-of-service approach and structuring consultations using a flipchart and prompts. Education and training were selected as the main intervention functions. For health providers, the delivery mode was webinar, to accommodate time and location constraints, bringing the training to the services; for patients, face-to-face consultations were supported by a booklet embedded with videos to improve patients' capability, opportunity and motivation. CONCLUSIONS: The ICAN QUIT in Pregnancy was an intervention to train health providers at Aboriginal Medical Services in how to implement culturally competent evidence-based practice including counselling and nicotine replacement therapy for pregnant patients who smoke. The BCW aided in scientifically and systematically informing this targeted implementation intervention based on the identified gaps in SCC by health providers. Multiple factors impact at systemic, provider, community and individual levels. This process was therefore important for defining the design and intervention components, prior to a conducting a pilot feasibility trial, then leading on to a full clinical trial.


Assuntos
Aconselhamento/métodos , Comportamentos Relacionados com a Saúde , Implementação de Plano de Saúde/métodos , Promoção da Saúde/métodos , Serviços de Saúde do Indígena , Abandono do Hábito de Fumar/métodos , Adulto , Austrália , Feminino , Humanos
5.
Midwifery ; 52: 27-33, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28570858

RESUMO

OBJECTIVE: One in two Indigenous Australian pregnant women smoke, yet little is known about their trajectory of smoking. This study aimed to explore Aboriginal women's narratives from starting smoking through to pregnancy. METHODS: A female Aboriginal Researcher conducted individual face-to-face interviews with 20 Aboriginal women from New South Wales, Australia. Recruitment, through Aboriginal services and community networks, continued until saturation was reached. Audio-recorded transcripts were independently open coded by two researchers, inductively analysed and reported using a three-dimensional structure of looking backwards, forwards, inwards, outwards and a sense of place, to elucidate the chronology of events, life stages, characters, environments, and turning points of the stories. RESULTS: A chronology emerged from smoking initiation in childhood, coming of age, becoming pregnant, through to attempts at quitting, and relapse post-partum. Several new themes emerged: the role mothers play in women's smoking and quitting; the contribution of nausea to spontaneous quitting; depression as a barrier to quitting; and the hopes of women for their own and their children's future. The epiphany of pregnancy was a key turning point for many - including the interplay of successive pregnancies; and the intensity of expressed regret. CONCLUSIONS: Aboriginal women report multiple influences in the progression of early smoking to pregnancy and beyond. Potential opportunities to intervene include: a) childhood, coming of age, pregnancy, post-natal, in-between births; b) key influencers; c) environments, and d) targeting concurrent substance use. Morning sickness appears to be a natural deterrent to continued smoking. Depression, and its relationship to smoking and quitting in Australian Indigenous pregnant women, requires further research.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Gestantes/psicologia , Fumantes/psicologia , Fumar/psicologia , Adolescente , Adulto , Austrália/etnologia , Feminino , Humanos , Narração , Grupos Populacionais/etnologia , Grupos Populacionais/psicologia , Gravidez , Gestantes/etnologia , Pesquisa Qualitativa , Fumar/efeitos adversos , Abandono do Hábito de Fumar/métodos , Abandono do Hábito de Fumar/psicologia
8.
BMC Cancer ; 7: 121, 2007 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-17608948

RESUMO

BACKGROUND: Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials. METHODS: The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software. RESULTS: Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. In vivo testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine. CONCLUSION: These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citosina/análogos & derivados , Desoxicitidina/análogos & derivados , Dioxolanos/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Citosina/administração & dosagem , Citosina/metabolismo , Citosina/farmacocinética , Desoxicitidina/administração & dosagem , Dioxolanos/metabolismo , Dioxolanos/farmacocinética , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Trítio/farmacocinética , Células Tumorais Cultivadas , Uridina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
9.
Mol Pharmacol ; 70(1): 303-10, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16617163

RESUMO

4'-Thio-beta-D-arabinofuranosyl cytosine (TaraC) is in phase I development for treatment of cancer. In human equilibrative nucleoside transporter (hENT) 1-containing CEM cells, initial rates of uptake (10 microM; picomoles per microliter of cell water per second) of [3H]TaraC and [3H]1-beta-D-arabinofuranosyl cytosine (araC) were low (0.007 +/- 003 and 0.034 +/- 0.003, respectively) compared with that of [3H]uridine (0.317 +/- 0.048), a highactivity hENT1 permeant. In hENT1- and hENT2-containing HeLa cells, initial rates of uptake (10 microM; picomoles per cell per second) of [3H]TaraC, [3H]araC, and [3H]deoxycytidine were low (0.30 +/- 0.003, 0.42 +/- 0.03, and 0.51 +/- 0.11, respectively) and mediated primarily by hENT1 (approximately 74, approximately 65, and approximately 61%, respectively). In HeLa cells with recombinant human concentrative nucleoside transporter (hCNT) 1 or hCNT3 and pharmacologically blocked hENT1 and hENT2, transport of 10 microM[3H]TaraC and [3H]araC was not detected. The apparent affinities of recombinant transporters (produced in yeast) for a panel of cytosine-containing nucleosides yielded results that were consistent with the observed low-permeant activities of TaraC and araC for hENT1/2 and negligible permeant activities for hCNT1/2/3. During prolonged drug exposures of CEM cells with hENT1 activity, araC was more cytotoxic than TaraC, whereas coexposures with nitrobenzylthioinosine (to pharmacologically block hENT1) yielded identical cytotoxicities for araC and TaraC. The introduction by gene transfer of hENT2 and hCNT1 activities, respectively, into nucleoside transport-defective CEM cells increased sensitivity to both drugs moderately and slightly. These results demonstrated that nucleoside transport capacity (primarily via hENT1, to a lesser extent by hENT2 and possibly by hCNT1) is a determinant of pharmacological activity of both drugs.


Assuntos
Arabinonucleosídeos/farmacocinética , Citarabina/farmacocinética , Proteínas de Transporte de Nucleosídeos/fisiologia , Animais , Arabinonucleosídeos/metabolismo , Arabinonucleosídeos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Citarabina/metabolismo , Citarabina/farmacologia , Citidina/análogos & derivados , Citidina/farmacologia , Relação Dose-Resposta a Droga , Transportador Equilibrativo 2 de Nucleosídeo/genética , Transportador Equilibrativo 2 de Nucleosídeo/fisiologia , Feminino , Células HeLa , Humanos , Potenciais da Membrana/fisiologia , Proteínas de Transporte de Nucleosídeos/genética , Oócitos/metabolismo , Oócitos/fisiologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Tioinosina/análogos & derivados , Tioinosina/farmacologia , Transfecção , Trítio , Uridina/farmacocinética , Xenopus laevis
10.
BMC Pharmacol ; 4: 8, 2004 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-15157282

RESUMO

BACKGROUND: Gemcitabine is an analogue of deoxycytidine with activity against several solid tumors. In order to elucidate the mechanisms by which tumor cells become resistant to gemcitabine, we developed the resistant subline RL-G from the human follicular lymphoma cell line RL-7 by prolonged exposure of parental cells to increasing concentrations of gemcitabine. RESULTS: In vitro, the IC50 increased from 0.015 microM in parental RL-7 cells to 25 microM in the resistant variant, RL-G. Xenografts of both cell lines developed in nude mice were treated with repeated injections of gemcitabine. Under conditions of gemcitabine treatment which totally inhibited the development of RL-7 tumors, RL-G derived tumors grew similarly to those of untreated animals, demonstrating the in vivo resistance of RL-G cells to gemcitabine. HPLC experiments showed that RL-G cells accumulated and incorporated less gemcitabine metabolites into DNA and RNA than RL-7 cells. Gemcitabine induced an S-phase arrest in RL-7 cells but not in RL-G cells. Exposure to gemcitabine induced a higher degree of apoptosis in RL-7 than in RL-G cells, with poly-(ADP-ribose) polymerase cleavage in RL-7 cells. No modifications of Bcl-2 nor of Bax expression were observed in RL-7 or RL-G cells exposed to gemcitabine. These alterations were associated with the absence of the deoxycytidine kinase mRNA expression observed by quantitative RT-PCR in RL-G cells. PCR amplification of désoxycytidine kinase gene exons showed a partial deletion of the dCK gene in RL-G cells. CONCLUSIONS: These results suggest that partial deletion of the dCK gene observed after selection in the presence of gemcitabine is involved with resistance to this agent both in vitro and in vivo.


Assuntos
Desoxicitidina Quinase/deficiência , Desoxicitidina Quinase/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma Folicular/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Desoxicitidina/farmacocinética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Deleção de Genes , Regulação Enzimológica da Expressão Gênica/fisiologia , Humanos , Linfoma Folicular/enzimologia , Linfoma Folicular/genética , Camundongos , Camundongos Nus , Transplante de Neoplasias/métodos , Ácidos Nucleicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transplante Heterólogo , Trítio/farmacocinética , Células Tumorais Cultivadas , Gencitabina
11.
Int J Cancer ; 107(1): 149-54, 2003 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-12925971

RESUMO

Adequate intracellular concentrations of ara-CMP, the monophosphorylated derivative of ara-C, are essential for its cytotoxicity. The critical step for ara-CMP formation is intracellular phosphorylation of ara-C by deoxycytidine kinase (dCK). A common nucleoside resistance mechanism is mutation affecting the expression or the specificity of dCK. We describe the ability of a tert-butyl S-acyl-thioethyl (SATE) derivative of ara-CMP (UA911) to circumvent ara-C resistance in a dCK-deficient human follicular lymphoma cell line (RL-G). The RL-G cell line was produced by continuous exposure to gemcitabine and displayed low dCK mRNA and protein expression that conferred resistance both to ara-C (2,250-fold) and to gemcitabine (2,092-fold). RL-G cells were able to take up the UA911 pronucleotide by diffusion and metabolize it to the corresponding ara-CMP and ara-CTP nucleotides, exhibiting a 199-fold reduction in resistance ratios, and a similar cell cycle arrest to the parental RL-7 cells. Exposures to 10, 50 or 100 microM concentrations of UA911 produced 160 +/- 7, 269 +/- 8 and 318 +/- 62 pmol ara-CTP/mg protein in RL-7 cells, and 100 +/- 12, 168 +/- 10 and 217 +/- 39 pmol ara-CTP/mg protein in RL-G cells, respectively. Exposure of RL-G cells to underivatized, radiolabeled ara-C produced no detectable amounts of the active triphosphate metabolites. We conclude that the UA911 pronucleotide is capable of overcoming dCK-mediated resistance. This result can be attributed to the unique cellular metabolism of the SATE pronucleotides giving rise to the intracellular delivery of ara-CMP to dCK-deficient cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Citarabina/farmacologia , Desoxicitidina Quinase/metabolismo , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Linfoma Folicular/tratamento farmacológico , Pró-Fármacos/farmacologia , Antimetabólitos Antineoplásicos/metabolismo , Arabinofuranosilcitosina Trifosfato/farmacologia , Divisão Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Desoxicitidina/farmacologia , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Gencitabina
13.
Leuk Lymphoma ; 43(7): 1435-40, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12389626

RESUMO

Gemcitabine is a cytotoxic nucleoside analog with activity in relapsing/refractory Hodgkin's disease (HD). Because gemcitabine is hydrophilic, it requires plasma membrane nucleoside transporter proteins to access intracellular targets. The most abundant and widely distributed transporter in human cells is human equilibrative nucleoside transporter 1 (hENT1). Because our prior studies showed that a deficiency in hENT1 confers high-level resistance to gemcitabine toxicity in vitro, we developed an immunohistochemical method to assess the hENT1 abundance of cells in tumor tissue. We now report the application of this method for visualizing the hENT1 protein abundance in the plasma membranes of Reed-Sternberg cells in lymph nodes of HD patients. Frozen sections of 30 lymph nodes were stained with monoclonal antibodies (mAb 10D7G2) raised against a synthetic peptide comprised of residues 254-271 from the large intracellular loop of hENT1 and staining intensity was scored on a 0-4 + scale. hENT1-staining intensity varied among HD lymph node samples (score/n; 0/8; 1/10; 2/9; 3/3; 4/0) and suggested that at least 60% of the tumors appeared hENT1 deficient. Because Epstein-Barr virus (EBV) is often associated with HD, staining for Epstein-Barr early RNA was also examined. Although 9/30 patients tested positive for EBV, there was no correlation with hENT1 staining. hENT1-staining intensities were positively correlated with age of the patient but were independent of other clinical, laboratory or pathology features (tumor stage, histologic subtype, presence of B symptoms, staining for CD15 or CD30, serum biochemistry, disease free survival, and overall survival). We conclude that, because hENT1 deficiency has been previously related to nucleoside-drug resistance, immunohistochemical staining for hENT1 warrants evaluation as a predictive tool for guiding the appropriate use of gemcitabine in the treatment of HD.


Assuntos
Transportador Equilibrativo 1 de Nucleosídeo/análise , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/metabolismo , Células de Reed-Sternberg/química , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Infecções por Vírus Epstein-Barr/diagnóstico , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Imuno-Histoquímica/métodos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem/normas , Estatísticas não Paramétricas
14.
Clin Cancer Res ; 8(1): 110-6, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11801546

RESUMO

Gemcitabine and capecitabine are nucleoside analogues used in chemotherapy strategies for the treatment of breast cancer. We previously demonstrated that deficiency in hENT1, the most abundant and widely distributed plasma membrane nucleoside transporter in human cells, confers high-level resistance to gemcitabine toxicity in vitro, whereas the relationship between hENT1 activity and capecitabine toxicity is unknown. To determine the relationship between capecitabine cytotoxicity and hENT1 abundance, cultured MDA-MB-435s human mammary carcinoma cells were exposed to graded concentrations of the capecitabine metabolites, 5'-deoxy-5-fluorouridine or 5-fluorouracil, in the presence and absence of nitrobenzylmercaptopurine ribonucleoside (NBMPR), a tight-binding inhibitor of hENT1. The presence of NBMPR reduced the cytotoxic effects of 5'-deoxy-5-fluorouridine, indicating that hENT1 also enabled cellular uptake of this capecitabine metabolite by breast cancer cells. We report here the development of an immunohistochemical method to assess the hENT1 abundance of malignant cells in solid tumors. Frozen sections of 33 primary breast cancers were stained with monoclonal antibodies raised against a synthetic peptide derived from the large intracellular loop of hENT1, and staining intensity was scored on a 0-4+ scale. hENT1 staining intensity varied markedly among breast samples (4 with score 0, 5 with score 1+, 7 with score 2+, 14 with score 3+, 3 with score 4+), suggesting that at least 9 of the tumors were hENT1 deficient. We conclude that because hENT1 deficiency has previously been associated with nucleoside drug resistance, immunohistochemical staining of hENT1 warrants further study as a predictive tool for guiding the appropriate use of gemcitabine and capecitabine in the treatment of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Desoxicitidina/análogos & derivados , Proteínas de Membrana Transportadoras/metabolismo , Tioinosina/análogos & derivados , Marcadores de Afinidade/farmacologia , Animais , Anticorpos Monoclonais , Formação de Anticorpos , Antimetabólitos Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Capecitabina , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/patologia , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Transportador Equilibrativo 1 de Nucleosídeo , Feminino , Floxuridina/efeitos adversos , Floxuridina/farmacologia , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Humanos , Técnicas Imunoenzimáticas , Camundongos , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Tioinosina/farmacologia
15.
Int J Cancer ; 97(4): 439-45, 2002 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11802204

RESUMO

Gemcitabine is a relatively new agent with promising activity in solid tumors. Few data are available regarding mechanisms of resistance to gemcitabine downstream from the drug-target interaction. The present study was performed to gain insight into the role of p53 status on the cytotoxicity of gemcitabine on cancer cells. Drug sensitivity, drug metabolism, cell kinetics and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the wildtype p53 (wt-p53) containing MN-1 cell line and, the MDD2 line containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to gemcitabine cytotoxicity than the MN-1 cell line. The resistant phenotype could not be attributed to a defective gemcitabine activation/degradation pathway or altered levels of expression of intracellular targets. Although both cell lines exhibited p53 accumulation, MN-1 but not MDD2 cells, displayed p21(WAF1) induction after exposure to gemcitabine. Gemcitabine induced an S-phase arrest in both cell lines. A more pronounced block in G1 phase, however, was observed in MN1 cells. Exposure to gemcitabine induced a higher degree of apoptosis in MN-1 than in MDD2 cells. This corresponded with suppression of Bcl-2 and Bcl-X/L expression in wt-p53 cells exposed to gemcitabine whereas Bcl-2 levels remained stable and Bcl-X/L levels increased in mut-p53 cells exposed to gemcitabine. We conclude that the p53 status of cancer cells influences their sensitivity to gemcitabine cytotoxicity. Our evidence suggests that loss of p53 function leads to loss of cell cycle control and alterations in the apoptotic cascade, conferring resistance to gemcitabine in cancer cell lines displaying a mut-p53.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Genes p53 , Proteínas de Neoplasias/fisiologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteína Supressora de Tumor p53/fisiologia , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ciclinas/genética , Dano ao DNA , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Dominantes , Genes bcl-2 , Humanos , Proteínas de Neoplasias/deficiência , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Fase S/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína bcl-X , Gencitabina
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