The positive role of thromboxane A2 (TxA2) and Its receptor in lung cancer cell growth induced by smoking carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK). / CUHK electronic theses & dissertations collectionJanuary 2012 (has links)
肺癌是一個世界性的健康難題。大量研究證據顯示，煙草及其致癌物NNK對環氧酶（COX）-2及其下游產物具有促進效應。血栓素（TxA）2是COX-2的關鍵性下游產物之一，該論文闡述了TxA2在NNK導致的肺癌增長中的可能作用。 / 我們發現相对于非吸烟者，吸煙者肺癌組織表达更高水平的TxA2合酶（TxAS）。NNK可以刺激培養的肺癌細胞TxA2合成。用TxAS抑制劑和TxA2受體（TP）拮抗劑分別阻抑TxA2的合成與功能可以引起細胞凋亡，從而有效抑制NNK導致的細胞增殖效應。在TxA2合成受抑制的情況下，TP激動劑U46619幾乎可以重建NNK效應，說明TP在NNK效應中的重要作用。研究還顯示，激活的TP可以通過PI3K/Akt和ERK通路進一步激活CREB，從而參與NNK對肺癌細胞的促生長效應。 / 緊接著，我們的研究顯示TP 可以調節NNK對COX-2 和TxA2的誘導，而且發現NNK刺激的TxA2合成主要依賴於COX-2活性。COX-2和TxA2功能抑製劑對NNK的促細胞生長作用具有相似的抑制效用。考慮到TP是TxA2的功能受體，該資料說明TP在NNK處理的肺癌細胞中傳遞了上游因子COX-2的促腫瘤作用。在使用COX-2小干擾RNA（siRNA）抑制NNK作用的情況下，TP激動劑U46619幾乎可以恢復NNK的效應證實了TP的傳遞者角色。研究還發現 TPα而不是TPβ在培養的肺癌細胞系中廣泛表達，並且過表達TPα具有促進腫瘤生長的作用。在用NNK處理細胞的條件下，TPα還具有促COX-2表達和TxA2生成的作用。 / 我們的研究進一步發現，在吸煙者肺癌組織中TPα表達增高，這與TxAS的表達相似。与此结果相一致，在經NNK處理的A/J小鼠肺癌組織中，TxAS和TP表達水準也是明顯上升的。在細胞培養實驗中，NNK能夠提高TxAS蛋白和信使RNA（mRNA）的表達水準。但是，在TP的兩個亞型TPα和TPβ中， NNK僅能促進TPα的蛋白表達，對它們的mRNA均無影響。NNK對TxAS的促表達作用是核轉錄因數(NF)-κB依賴性的。其他的幾個關鍵轉錄因數，諸如特異性蛋白(SP)-1，CREB和活化受體 （PPAR）γ均未參與NNK對TxAS和TPα的表達促進作用。進一步的，轉錄後機理被證實參與了NNK對TPα的作用。TPα而不是TPβ經鑒別在NNK的促NF-κB 激活 和 促TxAS 表達效應中起正向調節作用。 / 總之， 我們的研究說明TxA2相關通路在NNK的促肺癌細胞生長效應中起正向調節作用。我們的研究揭示了TPα的自我激活環路。通過該環路，TxA2，或者說TxAS和TPα參與了NNK的肺癌促生長效應。因此，我們的研究為肺癌的防治了提供了一個新的方向，即靶向TxAS和TPα是一種可能有效的策略。 / Lung cancer concerns a world-wide health problem. There is considerable evidence of that tobacco smoke and its carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) have the potential effects on the production of cyclooxygenase (COX)-2 and its downstream products in tumor cells. This thesis is constructed to describe the study focused on the role of thromboxane A2 (TxA2), one of the key downstream products of COX-2, in NNK-induced lung tumor growth. / We found that as compared to non-smokers, lung cancer tissues obtained from smokers tended to express more TxA2 synthase (TxAS). Moreover, NNK could stimulate TxA2 synthesis in lung cancer cells. Blockade of TxA2 synthesis and action by TxAS inhibitor and TxA2 receptor (TP) antagonist completely blocked NNK-promoted cell proliferation via inducing apoptosis. Moreover, TP agonist U46619 reconstituted a near full proliferative response to NNK when TxAS was inhibited, affirming the role of TP in NNK-induced cell growth. Furthermore, we revealed that the activated TP may then activate CREB through PI3K/Akt and ERK pathways, thereby contributing to the NNK-induced lung cancer cell growth. / We subsequently showed that TP could modulate the induction of COX-2 and TxA2 by NNK. The synthesis of TxA2 stimulated by NNK was found to be mainly dependent on COX-2 activity. Intriguingly, there are similar inhibitory effects on NNK-induced cell growth between pharmacological inhibition of COX-2 and the blockade of TxA2 synthesis and action. Because TP is the natural receptor of TxA2, these results suggest that TP may function as a mediator for the tumor-promoting effects of COX-2 upon NNK treatment, which was confirmed by the data showing that U46619 almost restored NNK effects in the presence of COX-2-siRNA. Importantly, TPα, but not TPβ was found to be widely expressed in lung cancer cells and be able to promote tumor growth, COX-2 expression and TxA2 synthesis upon NNK treatment. / We further demonstrated that in lung tumor tissues obtained from smoker, TPα protein was increased, which was similar to the change in TxAS protein. The increased levels of TxAS and TP proteins were also found in lung cancer tissues of A/J mice treated with NNK. In cell culture experiments, NNK could increase TxAS at both protein and mRNA levels. However, TPα rather than TPβ was increased by NNK at protein but not mRNA level. NNK-stimulated TxAS expression was dependent on nuclear factor (NF)-κB signaling. Other key transcriptional factors, such as specificity protein(SP)-1, CREB and peroxisome proliferator-activated receptor-gamma (PPARγ), were not involved in NNK-induced TxAS and TPα expression. Further experiments revealed that post-transcriptional mechanisms were responsible for NNK-induced TPα expression. TPα rather than TPβ was finally identified to have a positive role in NNK-induced NF-κB activation and TxAS expression. / Taken together, our study suggests that TxA2 pathway has a positive role in NNK-induced lung cancer cell growth. An auto-positive feedback loop of TPα activation to facilitate lung tumor growth in the presence of NNK is delineated by these results. Therefore, targeting TxAS or/and TPα may represent a promising strategy for prevention and treatment of lung cancer. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Huang, Runyue. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 119-146). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong,  System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.I / 摘要 / Publications / Acknowledgement / Abbreviations / Table of contents / Chapter Chapter 1 --- General introduction--Tobacco smoking, COX-2 pathway and cancer / Chapter 1.1 --- Abstract --- p.1 / Chapter 1.2 --- Introduction --- p.2 / Chapter 1.3 --- Cyclooxygenase and prostanoids --- p.5 / Chapter 1.4 --- The effects of tobacco smoking on COX-2 pathway, and the related pathologies --- p.8 / Chapter 1.4.1 --- Smoking, PGE2, inflammation and immunosupression --- p.8 / Chapter 1.4.2 --- Smoking, TxA2, platelet activation, cell contraction and angiogenesis --- p.11 / Chapter 1.4.3 --- Smoking and PGI2 --- p.16 / Chapter 1.5 --- The role of cyclooxygenase-2 pathway in the progression of tobacco smoke-related cancers --- p.19 / Chapter 1.5.1 --- Lung cancer --- p.19 / Chapter 1.5.2 --- Gastrointestinal cancer --- p.23 / Chapter 1.5.3 --- Bladder cancer --- p.24 / Chapter 1.5.4 --- Head and neck squamous cell carcinoma --- p.25 / Chapter 1.5.5 --- The signaling mechanisms underlying the induction of COX-2 by smoking in tumors --- p.26 / Chapter 1.6 --- Summary, future directions and key questions --- p.28 / Chapter Chapter 2 --- NNK induces lung cancer cell growth by stimulating TxA2 and its receptor / Chapter 2.1 --- Abstract --- p.32 / Chapter 2.2 --- Introduction --- p.33 / Chapter 2.3 --- Materials and Methods --- p.35 / Chapter 2.3.1 --- Cell lines and cell culture --- p.35 / Chapter 2.3.2 --- Chemicals and drug treatment --- p.35 / Chapter 2.3.3 --- Thromboxane B2 EIA assay --- p.36 / Chapter 2.3.4 --- MTT assay --- p.36 / Chapter 2.3.5 --- BrdU cell proliferation assay --- p.37 / Chapter 2.3.6 --- Flow cytometry for analysis of apoptosis --- p.37 / Chapter 2.3.7 --- Transfection of cells with CREB siRNA --- p.38 / Chapter 2.3.8 --- Western blot analysis and antibodies --- p.38 / Chapter 2.3.9 --- Statistical analysis --- p.39 / Chapter 2.4 --- Results --- p.41 / Chapter 2.4.1 --- High expression of TxAS in lung cancer tissues of smoker --- p.41 / Chapter 2.4.2 --- NNK stimulated TxA2 synthesis in lung cancer cells --- p.43 / Chapter 2.4.3 --- Blockade of TxA2 synthesis and action prevented NNK-induced cell growth --- p.44 / Chapter 2.4.4 --- TxA2 mimetic U46619 reconstituted NNK-enhanced cell proliferation under TxA2-inhibited condition --- p.47 / Chapter 2.4.5 --- Blockade of TxA2 synthesis or action induced the apoptosis of the NNK-exposed cells --- p.47 / Chapter 2.4.6 --- CREB is accountable for the key role of TxA2 in NNK-enhanced cell proliferation --- p.49 / Chapter 2.4.7 --- PI3K/Akt and ERK rather than JNK and p38 pathways were mediated by TxA2 in the NNK-exposed cells --- p.52 / Chapter 2.4.8 --- CREB is located downstream of the PI3K/Akt and ERK pathways in NNK-treated cells --- p.53 / Chapter 2.5 --- Discussion --- p.55 / Chapter Chapter 3 --- The positive role of TPα in the induction of COX-2, TxA2 and cell growth by NNK in human lung cancer cells / Chapter 3.1 --- Abstract --- p.62 / Chapter 3.2 --- Introduction --- p.63 / Chapter 3.3 --- Materials and methods --- p.65 / Chapter 3.3.1 --- Cell culture and chemicals --- p.65 / Chapter 3.3.2 --- Transient transfections --- p.66 / Chapter 3.3.3 --- TxB2 measurement --- p.66 / Chapter 3.3.4 --- Cell growth detection --- p.67 / Chapter 3.3.5 --- Analysis of apoptosis --- p.67 / Chapter 3.3.6 --- Western blot analysis and antibodies --- p.67 / Chapter 3.3.7 --- Statistical analysis --- p.68 / Chapter 3.4 --- Results --- p.70 / Chapter 3.4.1 --- Examination of TP as the modulator for induction of COX-2 and TxA2 by NNK --- p.70 / Chapter 3.4.2 --- The TxA2 generated in cells treated with NNK is mainly dependent on COX-2 activity --- p.72 / Chapter 3.4.3 --- Examination of TP as the key mediator for the tumor-promoting effect of COX-2 --- p.72 / Chapter 3.4.4 --- The expression and action of α and β isoforms of TP in human lung cancer cells --- p.77 / Chapter 3.4.5 --- the identification of positive role of TPα in NNK-induced COX-2, TxA2 and cell growth in lung cancer cells --- p.79 / Chapter 3.5 --- Discussion --- p.81 / Chapter Chapter 4 --- TP-α facilitates lung tumor growth through an autoregulatory feedback mechanism / Chapter 4.1 --- Abstract --- p.88 / Chapter 4.2 --- Introduction --- p.89 / Chapter 4.3 --- Materials and methods --- p.91 / Chapter 4.3.1 --- Human lung tissue and immunohistochemical analysis --- p.91 / Chapter 4.3.2 --- Animal treatment --- p.91 / Chapter 4.3.3 --- Cell culture and chemicals --- p.92 / Chapter 4.3.4 --- Transient transfection --- p.93 / Chapter 4.3.5 --- Real-time PCR --- p.93 / Chapter 4.3.6 --- Western blot analysis and antibodies --- p.94 / Chapter 4.3.7 --- Statistical analysis --- p.95 / Chapter 4.4 --- Results --- p.96 / Chapter 4.4.1 --- The effects of smoking on the expression of TP in human lung cancer tissue --- p.96 / Chapter 4.4.2 --- The effects of NNK on the expression of TxAS and TP in lung tissues of A/J mice --- p.98 / Chapter 4.4.3 --- The effects of NNK on the expression of TxAS and TPα in lung cancer cells --- p.99 / Chapter 4.4.4 --- Identification of the roles of NF-κB, CREB and SP1 in NNK-induced TxAS and TPα expression --- p.101 / Chapter 4.4.5 --- The negative role of PPARγ in NNK-induced TxAS and TPα expression --- p.104 / Chapter 4.4.6 --- NNK-induced TPα expression via post-transcriptional mechanism --- p.105 / Chapter 4.4.7 --- Examination of TPα auto-activation mechanism in lung cancer cells stimulated with NNK --- p.106 / Chapter 4.5 --- Discussion --- p.109 / Chapter Chapter 5 --- Conclusion and future works / Chapter 5.1 --- Conclusion --- p.114 / Chapter 5.2 --- Future works --- p.115 / Chapter 5.2.1 --- The possible role of miR-34c in the auto-regulatory loop of TxAS expression or TPα activation --- p.116 / Chapter 5.2.2 --- The possible role of FOXO3a in the auto-regulatory loop of TxAS expression or TPα activation --- p.116 / References --- p.119
Inflamação e câncer hepático e pulmonar em camundongos selecionados para máxima ou mínima resposta inflamatória aguda. / Inverse susceptibility to hepatic and lung cancer in mouse lines selected according to the acute inflammatory response.Lílian Rêgo de Carvalho 18 March 2013 (has links)
A inflamação é um componente essencial presente no microambiente tumoral, sendo relacionada a muitos tipos de câncer, como o de pulmão e de fígado. O objetivo foi estudar a influência de fatores genéticos relacionados à inflamação no desenvolvimento do câncer através da análise da progressão tumoral em camundongos AIRmax e AIRmin, geneticamente selecionados para máxima ou mínima resposta inflamatória. Os carcinomas foram induzidos pela injeção de Uretana ou DEN. 32 semanas após dose, a maioria dos AIRmax apresentaram tumores hepáticos, enquanto AIRmin foram resistentes. O contrário aconteceu com câncer de pulmão: todos os AIRmin foram acometidos e poucos AIRmax apresentaram pequenas lesões. As proteínas de fase aguda IL-6, TNF<font face=\"Symbol\">a e IL-1<font face=\"Symbol\">b são importantes nesse processo, pois tiveram aumento de produção em órgãos alvo horas após injeção. Esses resultados sugerem que um grupo de loci gênicos controla a resposta inflamatória e a susceptibilidade/resistência a diversos tipos de câncer e ressaltam o papel específico de células locais no controle da imunidade ao tumor. / Inflammatory components are an essential part of the tumor microenvironment being crucial in some types of cancer. Our objective was to study the influence of genetic factors relevant to inflammatory response regulation on cancer development by the comparative analysis of carcinogen-induced liver and lung tumors in AIRmax and AIRmin mouse strains, genetically selected for maximum and minimum inflammatory responsiveness. The carcinomas were induced by the injection of Urethane or DEN. 32 weeks after treatment, most AIRmax had liver tumors whereas AIRmin mice were resistant. The inverse occured in lungs: all AIRmin were affected and the incidence in AIRmax was 27.3%. The acute phase proteins IL-6, TNF<font face=\"Symbol\">a and IL-1<font face=\"Symbol\">b seem to be important in this process, with increased production in target organs hours after drug injection. These results provide a demonstration that a group of genes controls the inflammatory response and susceptibility or resistance to different types of cancers and also highlight the specific role of local cells in the control of tumor immunity.
"Contribuição à avaliação prognóstica de pacientes com adenocarcinoma pulmonar avançado: estudo imunohistoquímico da expressão do fator 1 de transcrição tireoideano e da metaloproteinase 9" / Contribution to the prognostic assessment of patients with advanced lung adenocarcinoma: evaluation by immunohistochemical methods of thyroid transcription factor-1 and matrix metalloproteinase-9Sandro José Martins 28 April 2005 (has links)
O valor prognóstico da expressão do Fator 1 de Transcrição Tireoideano (TTF-1) e da metaloproteinase-9 (MMP-9) foi avaliado em 51 pacientes com adenocarcinoma pulmonar avançado. Foram fatores de mau prognóstico: baixa capacidade funcional (P = 0,017), baixa expressão do TTF-1 (P = 0,001) e alta expressão da MMP-9 (P = 0,008). Identificaram-se três grupos de risco para mortalidade: baixo risco (TTF-1 > 40% e MMP-9 < 80%; sobrevida: 127,6 semanas), risco intermediário (TTF-1 < 40% ou MMP-9 > 80%; sobrevida: 39,0 semanas) e alto risco (TTF-1 < 40% e MMP-9 > 80%; sobrevida: 16,4 semanas). Com a detecção destes marcadores é possível a identificação de subgrupos de pacientes com prognósticos clinicamente distintos. / The prognostic value of Thyroid Transcription Factor-1 (TTF-1) and Matrix Metalloproteinase-9 (MMP-9) tumor expression was evaluated in 51 patients with advanced lung adenocarcinoma. Poor performance status (P = 0.017), low TTF-1 (P = 0.001), and high MMP-9 (P = 0.008) were independent prognostic factors. There was three risk groups: low risk (TTF-1 > 40% and MMP-9 < 80%; median survival: 127.6 wk), intermediate risk (TTF-1 < 40% or MMP-9 > 80%; median survival: 39.0 wk), and high risk (TTF-1 < 40% and MMP-9 > 80%; median survival: 16.4 wk). Evaluation of TTF-1 and MMP-9 may allow us to identify different, clinically meaningful, prognostic groups of lung adenocarcinoma patients.
The interactive transcript abundance index [c-Myc*p73alpha]/[p21*Bcl-2] correlates with spontaneous apoptosis and response to CPT-11 : implications for predicting chemoresistance and cytotoxicity to DNA damaging agentsHarr, Michael W. January 2007 (has links)
Thesis (Ph.D.)--University of Toledo, 2007. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: James Willey. Includes abstract. Title from title page of PDF document. Bibliography: pages 47-51, 73-76, 120-174.
The role of tumoral 1,25 dihydroxyvitamin D3 in inhibition of tumor growth and progression in the PyVMT MMTV#634 transgenic breast cancer model /Rossdeutscher, Lionel Philip David. January 2007 (has links)
Vitamin D3 must be metabolically activated by the liver to 25-hydroxyvitamin D3 (25OHD3) and then by the kidney 1alphahydroxylase (1alphaOHase) to become 1,25dihydroxyvitamin D 3 (1,25(OH)2D3). 1,25(OH)2 D3 is a potent inhibitor of tumor growth in vitro and in vivo. Recent studies indicate that metabolic activation of 1,25(OH) 2D3 also occurs in cancer cells such as breast cancer. Consequently, the major objective of this project was to determine if tumoral 25OHD 3-1alphahydroxylase modulates any or all of the stages of breast tumor progression without inducing the hypercalcemic side effects of 1,25(OH) 2D3. For this purpose we used the PyVMT breast cancer mouse model in which the oncoprotein, polyomamiddle T antigen (PyMT) is under the control of mouse mammary tumor virus LTR (MMTV LTR). Mice exhibited tumors restricted to the mammary epithelium progressing to the various stages of breast cancer. Animals were treated with either vehicle, 25OHD3 (2000 pM/24h) or 1,25(OH)2D3 (12pM/24h). Mice treated with the vitamin D precursor, 25OHD3, exhibited a marked reduction in tumor onset and growth comparable to the 1,25(OH)2D3 treated group. Furthermore, biomarkers of tumor progression were markedly reduced in 25OHD3 and 1,25(OH)2D3 animals as compared to vehicle-treated animals. However, mean circulating calcium concentrations remained unchanged in 25OHD3 treated animals but increased significantly in 1,25(OH)2D3 treated animals as compared to controls. Tumoral levels of 1,25(OH)2D3 in mice treated with 25OHD3 were increased 79% in comparison to vehicle control mice. Additionally, 25OHD3 and 1,25(OH)2D 3 treated animals had a significant decrease in the mean number of lung metastases per animal as compared to vehicle treated control animals. This study therefore suggests an important autocrine role of 1alphaOHase expression in breast tumor cells. Furthermore, accumulation of intra-tumoral 1,25(OH) 2D3 in response to 25OHD3 administration strongly suggests that locally produced 1,25(OH)2D3 plays a significant role in restraining tumor growth without inducing the hypercalcemic side effects associated with 1,25(OH)2D3.
Macrophage and bone marrow derived monocyte activation during mouse lung tumorigenesis and chronic inflammation /Redente, Elizabeth Frances. January 2008 (has links)
Thesis (Ph.D. in Toxicology) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 224-253). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
Bone metastases in lung cancer a clinical study in 200 consecutive patients with bronchogenic carcinoma and its therapeutic implications for small cell carcinoma /Hansen, Heine Høi. January 1974 (has links)
Thesis--Copenhagen. / Summary in Danish. Includes bibliographical references (p. 202-221) and index.
Fujiwara, Atsuko. Roberts, Robert E., Forman, Michele R. Felknor, Sarah Anne.
Thesis (M.P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 2008. / Source: Masters Abstracts International, Volume: 47-01, page: . Advisers: Robert E. Roberts; Michele Forman. Includes bibliographical references.
Lesões em DNA promovidas por produtos de oxidação do β-caroteno: possíveis implicações biológicas / Lesions in DNA caused by oxidation products of -carotene: possible biological implicationsSabrina de Almeida Marques 11 May 2005 (has links)
Apesar de diversos estudos in vitro e em populações indicarem um efeito protetor do β-caroteno em sistemas biológicos, estudos epidemiológicos como o \"The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study\" (ATBC) e o \"The Beta-Carotene and Retinol Efficacy Trial\" (CARET) mostraram um aumento na incidência de câncer pulmonar em indivíduos fumantes suplementados com β-caroteno. Essa ação contraditória tem sido chamada na literatura de \"Paradoxo do β-Caroteno\". Sabe-se que este carotenóide sob altas pressões de oxigênio ou na presença de peróxidos pode sofrer oxidação e levar a formação de compostos como aldeídos, epóxidos, etc, que são capazes de se adicionarem covalentemente ao DNA. Estudos, in vitro e in vivo têm demonstrado a possibilidade de os metabólitos do β-caroteno agirem como agentes pró-carcinogênicos. Estes agentes quando ativados quimicamente podem levar à formação de adutos de DNA. Já se sabe que alguns desses adutos encontramse em níveis aumentados em diversas situações de risco de câncer. Diversos grupos, incluindo o nosso, têm demonstrado a formação de lesões em DNA a partir de aldeídos e epóxidos exógenos ou gerados endogenamente. O presente trabalho mostra que a reação do β-caroteno e dois de seus produtos de oxidação, retinal e β-apo-8\'-carotenal, com 2\'-desoxiguanosina e DNA leva à formação de adutos. Dentre os adutos formados, foi caracterizado o aduto 1,N2eteno-2\'-desoxiguanosina (1 ,N2-εdGuo). Os níveis de outro aduto de DNA, a 8-oxo-7,8-dihidro-2\'-deoxiguanosina (8-oxodGuo), também foram monitoradas para estudo comparativo. A formação dos adutos também foi verificada em fibroblastos normais de pulmão humano (linhagem IMR-90) expostos ao β-caroteno e aos seus produtos de oxidação. Experimentos com ratos suplementados com β-caroteno e expostos à fumaça de cigarro em períodos de 7, 30 e 180 dias, mostraram níveis aumentados de 1,N2-εdGuo nos animais suplementados com o carotenóide comparado ao grupo veículo. Aumento no nível de 8-oxodGuo também foi verificado nos tratamentos de 7 e 180 dias. Um aumento significativo no nível do eteno aduto também foi verificado nos animais suplementados com β-caroteno e expostos à fumaça de cigarro, comparado ao grupo apenas exposto à fumaça após 7 e 180 dias de exposição. Nestes mesmos grupos, o aumento do 8-oxodGuo só foi observado no tratamento por 180 dias. Sabendo que estas lesões são comprovadamente mutagênicas, nossos estudos podem contribuir para o esclarecimento dos mecanismos envolvidos na formação de câncer em fumantes suplementados ou não com β-caroteno. / Despite several studies performed in vitro and in population indicate a protector effect of β-carotene, the epidemiological studies \"The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study\" (ATBC) and \"The Beta-Carotene and Retinol Efficacy Trial\" (CARET) showed a relative risk for lung cancer in smokers supplemented with β-carotene. It is well known that this carotenoid is able to oxidize in high oxygen tension or in the presence of peroxides yielding to aldehydes, epoxides, and other compounds that are capable to bind to DNA. lhe possibility that β-carotene oxidation products can act as pro carcinogenic agents is under investigation. Lhese products can be activated by peroxides, ar by enzymes such as cytochromr P450, leading to DNA adducts formation. Several groups, like ours, showed the formation of DNA adducts from aldehydes or epoxides generated by endogenous or exogenous sources. We investigated here the reactions of β-carotene, and two of its oxidation products, retinal and β-apo-8\'-carotenal, with 2\'-deoxyguanosine to evaluate their DNA damaging potential. A known mutagenic adduct, 1,N2-etheno-2\'-deoxyguanosine (1 ,N2 edGuo) was isolated and characterized on the basis of its spectroscopic features. After treatment of calf thymus DNA with β-carotene or β-carotene oxidation products, significantly increased levels of the etheno adduct were detected and quantified in DNA by a sensitive LC/ESI/MS-MS technique. For comparative purposes, levels of 8-oxo7,8-dihydro-2\'-deoxyguanosine were also evaluated (8-oxodGuo). Levels of these lesions were also increased. Exposure of human lung cells (IMR 90) to the carotenoids also leads to increased levels of the two adducts. As the main noteworthy result, rats supplemented with β-carotene for 7, 30, and 180 days showed significantly higher lung DNA concentrations of the 1,N2-εdGuo adduct than those of the control group. lhe level of 8-oxodGuo was also increased after 7 and 180 days in the group supplemented with the carotenoid. Rats supplemented with β-carotene and exposed to cigarette smoke for 7 and 180 days also showed significantly increased levels of the adduct 1,N2-εdGuo when compared with the group exposed to cigarette smoke. In the same groups level of 8-oxodGuo was only increased after 180 days of treatment. These DNA lesions are confirmed mutagenic, so our data could contribute to the elucidation of the mechanisms responsible for the association between β-carotene and lung cancer in smokers.
Avaliação da função pulmonar e da qualidade de vida em pacientes submetidos à ressecção pulmonar por neoplasia / Assessment of lung function and quality of life in patients submitted to lung resection for cancerLuciana Nunes Titton Lima 10 September 2008 (has links)
Introdução: A ressecção pulmonar pode ser seguramente realizada em pacientes com função pulmonar comprometida se eles forem selecionados apropriadamente, sendo importante determinar o impacto do procedimento cirúrgico no estado funcional e nas atividades de vida diária do paciente. Objetivo: Avaliar as repercussões da ressecção pulmonar sobre a espirometria e sobre a qualidade de vida de pacientes com câncer de pulmão. Métodos: Estudo de coorte transversal que incluiu todos pacientes que realizaram cirurgia com ressecção pulmonar entre Setembro de 2006 e março de 2007, após assinar o termo de consentimento livre e esclarecido. Os pacientes foram avaliados no pré-operatório e após seis meses do procedimento cirúrgico através de espirometria e responderam a dois questionários de qualidade de vida: um geral -The Medical Outcomes Study 36-item Short-Form Health Survey e um específico para sintomas respiratórios - Hospital Saint George. Resultados: Concluíram o estudo 33 pacientes, 14 homens e 19 mulheres com faixa etária entre 39 e 79 anos. Todos os pacientes independentemente de fumantes ou não, apresentaram piora significante da função pulmonar. Na análise de qualidade de vida, observamos valores próximos à população normal, e no questionário específico para doenças respiratórias foi observada redução de 50 a 60% nos vários domínios, em relação a uma população de DPOC. Conclusão: Existe impacto direto da ressecção pulmonar na deterioração da espirometria e na qualidade de vida com ênfase nos aspectos diretamente ligados à função pulmonar. Cabe ressaltar a importância da avaliação da função pulmonar destes pacientes no pré-operatório para se estimar sua evolução pós-cirúrgica / Introduction: Lung resection can be performed safely in patients with compromised lung function if properly selected. It is important to determine the impact of surgical procedure in the functional status and daily life activities, aiming at improving quality of life. Objective: Evaluate the effects of pulmonary resection on spirometry and the impact of surgery for lung cancer on patients quality of life. Methods: Prospective study, conducted between September 2006 and March 2007; all patients who performed pulmonary resection surgery were included after signing a free informed consent term. Patients were evaluated in the pre-operative and after six months of the surgical procedure by spirometry and answered two quality of life questionnaires (The medical Outcomes Study 36-item Short-form Health Survey and Saint George Hospital). Results: 33 patients concluded this study; 14 men and 19 women, age between 39 and 79 years. All patients smokers or not, showed worsening of lung function with statistical significance. General QOL scales showed near normal values, nevertheless, respiratory QOL was 50 to 60% worse than COPD. Conclusions: We observed a direct impact of lung resection on spirometry and QOL. It is important to adequately estimate lung and QOL function before assuming lung resection in cancer patients
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