Os estudos epidemiológicos relativos ao denominado câncer ocupacional têm como objetivo o estudo do câncer em populações trabalhadoras e a identificação de fatores causais. O número de agentes que comprovadamente causam câncer em seres humanos é ainda pequeno, cerca de trinta. A estes fatores podem ser agregados algumas atividades ocupacionais e processos industriais onde agentes potencialmente cancerígenos existem mas não foram ainda identificados. A quase totalidade dos estudos epidemiológicos buscando relacionar ocupação e câncer foram realizados nos países desenvolvidos, com processos de industrialização mais antigos e consolidados. Nesta investigação o objetivo é estudar a relação trabalho e câncer no contexto de um país subdesenvolvido e recentemente industrializado. O estudo explora os riscos ocupacionais determinantes da neoplasia pulmonar na Região Metropolitana de São Paulo (RMSP). O trabalho está dividido em duas partes. Na primeira são discutidos aspectos relativos ao câncer com particular destaque ao carcinoma broncogênico e à aplicação da metodologia epidemiológica na área da saúde do trabalhador, em especial para o estudo do câncer relacionado à ocupação. A segunda parte contempla a descrição do estudo de caso-controle construído para atingir os objetivos definidos. Os dados do estudo foram levantados no período de 1º de julho de 1990 a 31 de janeiro de 1991 em quatorze hospitais que concentram o atendimento a pacientes com câncer de pulmão na RMSP. Um total de 316 casos e 536 controles, emparelhados com os casos por sexo e idade, foram selecionados para análise. Tabagismo, tabagismo passivo, história migratória, outros cânceres na família e estrato sócio-econômico, além de sexo e idade, foram as outras variáveis estudadas. A análise univariada permitiu identificar as variáveis que estavam interferindo na relação principal estudada. Posteriormente, utilizou-se as técnicas de análise estratificada e de regressão logística para controlar as variáveis tabagismo, referência à carcinoma de pulmão na família, sexo e idade. Os resultados revelam que os trabalhadores que estiveram ligados por tempo prolongado aos setores de produção, de ramos de atividades industriais nos quais há maior probabilidade de exposição à substâncias cancerígenas, têm cerca de duas vezes o risco de desenvolverem carcinoma broncogênico em relação aos trabalhadores com menor probabilidade de exposição a substâncias cancerígenas como os que referiram nunca terem trabalhado fora de casa. / Epidemiological studies on occupational cancer have as their objective the study of cancer in working populations and the distribution of causal factors. The number of agents proved to cause cancer in humans is still rather small, about thirty. It could be added some occupational activities and industrial processes where hazardous agents are known to exist, but have not been identified. Almost all epidemiological studies to evaluate the relationship between occupation and cancer were carried out in developed countries, where industrialization process is older and more structured. In this investigation the objective is to study the association between occupation and cancer in a developing and newly industrialized country context. In this sense, the study explores occupational risks for lung cancer in the Metropolitan Region of São Paulo (MRSP). This work is split in two parts. Firstly it was introduced a review of some aspects on cancer, particularly lung cancer, and the use of epidemiologic methodology related to worker\'s health, particularly cancer. In the second part it was described the hospital-based case-control study carried out to reach defined objectives. This research was conducted between 1st July 1990 and 31st January 1991 in fourteen hospitais which concentrate lung cancer cases in the MRSP. It has been selected a total of 316 cases and 536 controls, matched by hospital, sex and age with cases. Smoking, passive smoking, migratory history, cancer in the family and socio-economic status, besides sex and age, were other variables studied. Univariate analysis identified variables that could interfere in the main studied associatian. Through stratification and logistic regression approaches the variables gender and age, smoking and reference to lung neoplasy in family, were controlled. The results showed that workers linked to the production sectors of industries where there are higher risk of exposure to carcinogenic products have about two fold the risk of developing lung cancer rather than those workers with the lowest risk of exposure to carcinogens.

Base teórica: O câncer de pulmão é uma doença com alta incidência e mortalidade, cujo prognóstico permanece discreto apesar do melhor entendimento da doença nas últimas décadas. A radioterapia tem papel terapêutico em todos os estágios da doença. A expressão da cofilina-1, uma proteína relacionada à mobilidade celular, determinou maior radiossensibilidade a células de adenocarcinoma brônquico em estudos in vitro, porém pior sobrevida em estádios iniciais Objetivo: Avaliar se a expressão da cofilina-1 interfere na sobrevida e no controle local em pacientes com câncer de pulmão submetidos a tratamento com radioterapia definitiva Métodos: Foram avaliados pacientes com câncer de pulmão não pequenas células, com estádios I–IV, que receberam radioterapia exclusiva ou combinada com quimioterapia, dirigida à neoplasia brônquica, na unidade de radioterapia do HCPA, nos anos de 2009 a 2015. Todos os pacientes tiveram a expressão de cofilina-1 aferida e foram distribuídos conforme os níveis de expressão de cofilina-1 utilizando-se de protocolo específico. Os prontuários foram avaliados retrospectivamente para calcular a sobrevida mediana. A progressão foi verificada através de avaliação de tomografias de tórax de controle. Resultados: Foram avaliados 45 pacientes neste estudo. A sobrevida mediana de todos os pacientes foi de 11,3 meses e a sobrevida global em 5 anos de 17,3%. Pacientes com expressão média ou alta de cofilina-1 tiveram maior mortalidade quando comparados com pacientes com baixa expressão (respectivamente, HR 1,628, IC95 1,137-8,287 e HR 1,59 IC95 1,105-7,342). Não houve diferença significantemente estatística entre controle local e expressão de cofilina-1. Conclusão: A expressão de cofilina-1 está associada à sobrevida em pacientes com carcinoma brônquico tratados com radioterapia e existe uma tendência a melhor controle local com baixa expressão. Nossos resultados sugerem um novo campo a ser explorado no manejo do carcinoma de pulmão localmente avançado, utilizando-se dos níveis de cofilina-1. / Background: Lung cancer is a disease with high incidence and mortality, whose prognosis remains poor despite a better understanding of the disease in the last decades. Radiotherapy plays a therapeutic role in all stages of disease. The expression of cofilin-1, a protein related to cellular mobility, determined greater radiosensitivity to lung adenocarcinoma cells in in vitro studies, but worse survival at initial stages. Objective: To evaluate if the expression of cofilin-1 modified survival and local control in lung cancer patients submitted to definitive treatment with radiotherapy. Methods: Patients with non-small cell lung cancer with stage IIV who received radiotherapy alone or combined with chemotherapy for lung cancer at the HCPA radiotherapy unit from 2009 to 2015 were evaluated. All patients had the expression of measured cofilin-1 evaluated and were distributed by cofilin-1 expression according to specific protocol. The medical records were retrospectively evaluated to estimate median survival. The progression was verified through evaluation of control chest tomography. Results: 45 patients were assessed in this study. The median survival of all patients was 11.3 months and the 5-year overall survival was 17.3%. Patients with medium or high expression of cofilin-1 had higher mortality rates when compared to patients with low expression (HR, 1,628, CI95, 1,137-8,287 and HR, 1.59, CI95, 1,105-7,342). There was no statistically significant difference between local control and cofilin-1 expression. Conclusion: cofilin-1 expression is associated with survival in patients with lung cancer treated with radiotherapy and there is a tendency for better local control with low CFL1 expression. Our results suggest a new field to be explored in the management of locally advanced lung carcinoma, using cofilin-1 expression levels.

Base teórica: O câncer de pulmão é uma doença com alta incidência e mortalidade, cujo prognóstico permanece discreto apesar do melhor entendimento da doença nas últimas décadas. A radioterapia tem papel terapêutico em todos os estágios da doença. A expressão da cofilina-1, uma proteína relacionada à mobilidade celular, determinou maior radiossensibilidade a células de adenocarcinoma brônquico em estudos in vitro, porém pior sobrevida em estádios iniciais Objetivo: Avaliar se a expressão da cofilina-1 interfere na sobrevida e no controle local em pacientes com câncer de pulmão submetidos a tratamento com radioterapia definitiva Métodos: Foram avaliados pacientes com câncer de pulmão não pequenas células, com estádios I–IV, que receberam radioterapia exclusiva ou combinada com quimioterapia, dirigida à neoplasia brônquica, na unidade de radioterapia do HCPA, nos anos de 2009 a 2015. Todos os pacientes tiveram a expressão de cofilina-1 aferida e foram distribuídos conforme os níveis de expressão de cofilina-1 utilizando-se de protocolo específico. Os prontuários foram avaliados retrospectivamente para calcular a sobrevida mediana. A progressão foi verificada através de avaliação de tomografias de tórax de controle. Resultados: Foram avaliados 45 pacientes neste estudo. A sobrevida mediana de todos os pacientes foi de 11,3 meses e a sobrevida global em 5 anos de 17,3%. Pacientes com expressão média ou alta de cofilina-1 tiveram maior mortalidade quando comparados com pacientes com baixa expressão (respectivamente, HR 1,628, IC95 1,137-8,287 e HR 1,59 IC95 1,105-7,342). Não houve diferença significantemente estatística entre controle local e expressão de cofilina-1. Conclusão: A expressão de cofilina-1 está associada à sobrevida em pacientes com carcinoma brônquico tratados com radioterapia e existe uma tendência a melhor controle local com baixa expressão. Nossos resultados sugerem um novo campo a ser explorado no manejo do carcinoma de pulmão localmente avançado, utilizando-se dos níveis de cofilina-1. / Background: Lung cancer is a disease with high incidence and mortality, whose prognosis remains poor despite a better understanding of the disease in the last decades. Radiotherapy plays a therapeutic role in all stages of disease. The expression of cofilin-1, a protein related to cellular mobility, determined greater radiosensitivity to lung adenocarcinoma cells in in vitro studies, but worse survival at initial stages. Objective: To evaluate if the expression of cofilin-1 modified survival and local control in lung cancer patients submitted to definitive treatment with radiotherapy. Methods: Patients with non-small cell lung cancer with stage IIV who received radiotherapy alone or combined with chemotherapy for lung cancer at the HCPA radiotherapy unit from 2009 to 2015 were evaluated. All patients had the expression of measured cofilin-1 evaluated and were distributed by cofilin-1 expression according to specific protocol. The medical records were retrospectively evaluated to estimate median survival. The progression was verified through evaluation of control chest tomography. Results: 45 patients were assessed in this study. The median survival of all patients was 11.3 months and the 5-year overall survival was 17.3%. Patients with medium or high expression of cofilin-1 had higher mortality rates when compared to patients with low expression (HR, 1,628, CI95, 1,137-8,287 and HR, 1.59, CI95, 1,105-7,342). There was no statistically significant difference between local control and cofilin-1 expression. Conclusion: cofilin-1 expression is associated with survival in patients with lung cancer treated with radiotherapy and there is a tendency for better local control with low CFL1 expression. Our results suggest a new field to be explored in the management of locally advanced lung carcinoma, using cofilin-1 expression levels.

Os estudos epidemiológicos relativos ao denominado câncer ocupacional têm como objetivo o estudo do câncer em populações trabalhadoras e a identificação de fatores causais. O número de agentes que comprovadamente causam câncer em seres humanos é ainda pequeno, cerca de trinta. A estes fatores podem ser agregados algumas atividades ocupacionais e processos industriais onde agentes potencialmente cancerígenos existem mas não foram ainda identificados. A quase totalidade dos estudos epidemiológicos buscando relacionar ocupação e câncer foram realizados nos países desenvolvidos, com processos de industrialização mais antigos e consolidados. Nesta investigação o objetivo é estudar a relação trabalho e câncer no contexto de um país subdesenvolvido e recentemente industrializado. O estudo explora os riscos ocupacionais determinantes da neoplasia pulmonar na Região Metropolitana de São Paulo (RMSP). O trabalho está dividido em duas partes. Na primeira são discutidos aspectos relativos ao câncer com particular destaque ao carcinoma broncogênico e à aplicação da metodologia epidemiológica na área da saúde do trabalhador, em especial para o estudo do câncer relacionado à ocupação. A segunda parte contempla a descrição do estudo de caso-controle construído para atingir os objetivos definidos. Os dados do estudo foram levantados no período de 1º de julho de 1990 a 31 de janeiro de 1991 em quatorze hospitais que concentram o atendimento a pacientes com câncer de pulmão na RMSP. Um total de 316 casos e 536 controles, emparelhados com os casos por sexo e idade, foram selecionados para análise. Tabagismo, tabagismo passivo, história migratória, outros cânceres na família e estrato sócio-econômico, além de sexo e idade, foram as outras variáveis estudadas. A análise univariada permitiu identificar as variáveis que estavam interferindo na relação principal estudada. Posteriormente, utilizou-se as técnicas de análise estratificada e de regressão logística para controlar as variáveis tabagismo, referência à carcinoma de pulmão na família, sexo e idade. Os resultados revelam que os trabalhadores que estiveram ligados por tempo prolongado aos setores de produção, de ramos de atividades industriais nos quais há maior probabilidade de exposição à substâncias cancerígenas, têm cerca de duas vezes o risco de desenvolverem carcinoma broncogênico em relação aos trabalhadores com menor probabilidade de exposição a substâncias cancerígenas como os que referiram nunca terem trabalhado fora de casa. / Epidemiological studies on occupational cancer have as their objective the study of cancer in working populations and the distribution of causal factors. The number of agents proved to cause cancer in humans is still rather small, about thirty. It could be added some occupational activities and industrial processes where hazardous agents are known to exist, but have not been identified. Almost all epidemiological studies to evaluate the relationship between occupation and cancer were carried out in developed countries, where industrialization process is older and more structured. In this investigation the objective is to study the association between occupation and cancer in a developing and newly industrialized country context. In this sense, the study explores occupational risks for lung cancer in the Metropolitan Region of São Paulo (MRSP). This work is split in two parts. Firstly it was introduced a review of some aspects on cancer, particularly lung cancer, and the use of epidemiologic methodology related to worker\'s health, particularly cancer. In the second part it was described the hospital-based case-control study carried out to reach defined objectives. This research was conducted between 1st July 1990 and 31st January 1991 in fourteen hospitais which concentrate lung cancer cases in the MRSP. It has been selected a total of 316 cases and 536 controls, matched by hospital, sex and age with cases. Smoking, passive smoking, migratory history, cancer in the family and socio-economic status, besides sex and age, were other variables studied. Univariate analysis identified variables that could interfere in the main studied associatian. Through stratification and logistic regression approaches the variables gender and age, smoking and reference to lung neoplasy in family, were controlled. The results showed that workers linked to the production sectors of industries where there are higher risk of exposure to carcinogenic products have about two fold the risk of developing lung cancer rather than those workers with the lowest risk of exposure to carcinogens.

Base teórica: O câncer de pulmão é uma doença com alta incidência e mortalidade, cujo prognóstico permanece discreto apesar do melhor entendimento da doença nas últimas décadas. A radioterapia tem papel terapêutico em todos os estágios da doença. A expressão da cofilina-1, uma proteína relacionada à mobilidade celular, determinou maior radiossensibilidade a células de adenocarcinoma brônquico em estudos in vitro, porém pior sobrevida em estádios iniciais Objetivo: Avaliar se a expressão da cofilina-1 interfere na sobrevida e no controle local em pacientes com câncer de pulmão submetidos a tratamento com radioterapia definitiva Métodos: Foram avaliados pacientes com câncer de pulmão não pequenas células, com estádios I–IV, que receberam radioterapia exclusiva ou combinada com quimioterapia, dirigida à neoplasia brônquica, na unidade de radioterapia do HCPA, nos anos de 2009 a 2015. Todos os pacientes tiveram a expressão de cofilina-1 aferida e foram distribuídos conforme os níveis de expressão de cofilina-1 utilizando-se de protocolo específico. Os prontuários foram avaliados retrospectivamente para calcular a sobrevida mediana. A progressão foi verificada através de avaliação de tomografias de tórax de controle. Resultados: Foram avaliados 45 pacientes neste estudo. A sobrevida mediana de todos os pacientes foi de 11,3 meses e a sobrevida global em 5 anos de 17,3%. Pacientes com expressão média ou alta de cofilina-1 tiveram maior mortalidade quando comparados com pacientes com baixa expressão (respectivamente, HR 1,628, IC95 1,137-8,287 e HR 1,59 IC95 1,105-7,342). Não houve diferença significantemente estatística entre controle local e expressão de cofilina-1. Conclusão: A expressão de cofilina-1 está associada à sobrevida em pacientes com carcinoma brônquico tratados com radioterapia e existe uma tendência a melhor controle local com baixa expressão. Nossos resultados sugerem um novo campo a ser explorado no manejo do carcinoma de pulmão localmente avançado, utilizando-se dos níveis de cofilina-1. / Background: Lung cancer is a disease with high incidence and mortality, whose prognosis remains poor despite a better understanding of the disease in the last decades. Radiotherapy plays a therapeutic role in all stages of disease. The expression of cofilin-1, a protein related to cellular mobility, determined greater radiosensitivity to lung adenocarcinoma cells in in vitro studies, but worse survival at initial stages. Objective: To evaluate if the expression of cofilin-1 modified survival and local control in lung cancer patients submitted to definitive treatment with radiotherapy. Methods: Patients with non-small cell lung cancer with stage IIV who received radiotherapy alone or combined with chemotherapy for lung cancer at the HCPA radiotherapy unit from 2009 to 2015 were evaluated. All patients had the expression of measured cofilin-1 evaluated and were distributed by cofilin-1 expression according to specific protocol. The medical records were retrospectively evaluated to estimate median survival. The progression was verified through evaluation of control chest tomography. Results: 45 patients were assessed in this study. The median survival of all patients was 11.3 months and the 5-year overall survival was 17.3%. Patients with medium or high expression of cofilin-1 had higher mortality rates when compared to patients with low expression (HR, 1,628, CI95, 1,137-8,287 and HR, 1.59, CI95, 1,105-7,342). There was no statistically significant difference between local control and cofilin-1 expression. Conclusion: cofilin-1 expression is associated with survival in patients with lung cancer treated with radiotherapy and there is a tendency for better local control with low CFL1 expression. Our results suggest a new field to be explored in the management of locally advanced lung carcinoma, using cofilin-1 expression levels.

Le cancer du poumon est la principale cause de décès par cancer chez les hommes et les femmes dans le monde. Malgré les avancées majeures dans les traitements, les thérapies à base de platine restent la thérapie standard pour les patients atteints du cancer du poumon induit par la mutation KRAS. Bien que les composés de platine aient un premier effet sur ces patients, l’apparition d’une rechute constitue le principal défi au niveau clinique.Dans ce contexte, notre projet actuel vise à caractériser l’activation de la voie Notch dans la réponse aux sels de platines d’adénocarcinomes mutés pour K-Ras ainsi que son rôle dans l’acquisition de la résistance à ce traitement. Nous avons mis en évidence que la voie Notch est activée en réponse à divers agents induisant des dommages à l’ADN dans des lignées de cancer du poumon. Nous avons montré que cette activation est dépendante de la voie de checkpoint de Réponse aux Dommages de l’ADN (DDR) via ATM, ATM qui est une des principales kinases de la réponse cellulaire aux lésions de l’ADN telles que les cassures double-brin, causé notamment par la chimiothérapie conventionnelle. Parmi les nombreux substrats d’ATM en réponse à ces dommages, nous montrons un effet direct de MDM2 dans l’activation de la voie Notch en réponse aux dommages à l’ADN causé par le carboplatine. Nos données montrent une nouvelle interaction entre ATM, MDM2 et Notch, lors du traitement au carboplatine, qui pourrait jouer un rôle dans la cascade de signalisation favorisant la survie des cellules tumorales pulmonaires.En utilisant des xénogreffes dérivées de patients atteints d’adénocarcinomes du poumon, ainsi qu’un modèle cellulaire de xénogreffe résistant à la carboplatine, nous avons montré que l’association d’inhibiteurs de Notch et de MDM2 associé au traitement au carboplatine ont un effet accru sur le ralentissement de la croissance de la tumeur et sur la survie, en comparaison avec le traitement actuel de référence que représente le carboplatine.Nos résultats offrent une nouvelle possibilité de thérapie pour les adénocarcinomes de poumons mutés pour KRAS, et pourrait donc répondre à un besoin clinique urgent notamment pour contrecarrer la résistance aux chimiothérapies conventionnelles à base de sels de platine. / Lung cancer is the leading cause of cancer death among men and women worldwide. Despite the major advances in the treatments, platinum-based therapy remains the standard of care for patients affected by KRAS-driven lung cancer. Even though the platinum-compounds display an initial effect on these patients, the onset of the relapse constitutes the main challenge for the clinic. The molecular mechanisms underlying lung adenocarcinoma (LUAD) relapse are not completely elucidated yet, thus it is fundamental to understand them in order to improve survival of patients. Our data show that upon carboplatin treatment, the Notch pathway is activated in vitro. Since this effect was common for several other DNA damage insults, our driving hypothesis connected the DNA Damage Response (DDR) to the activation of the Notch pathway. Our data demonstrates that protein kinase ataxia telangiectasia-mutated (ATM) is a key mediator in the activation of the Notch pathway during DNA damage signalling. ATM is well-known as the chief mobilizer of the cellular response to the most toxic lesions to the DNA, the double-strand breaks which are also the type of damage caused by the conventional chemotherapy. Among the several substrates of ATM in response to the damage, there is the mouse double minute 2 protein (MDM2) that it is known to interact with the Notch pathway. Our data uncovered a new pathway connecting ATM, MDM2 and NICD during carboplatin treatment in LUAD cells.Using LUAD Patient-Derived Xenografts and a new generated carboplatin resistant cellular model, we show in vivo that the combination of Notch and MDM2 inhibitors with carboplatin showed a therapeutic benefit in tumour growth and survival compared to the standard of care, i.e. carboplatin.Our results can offer a new therapeutic window for KRAS-driven LUAD that become resistant to platinum-based therapy, hence tackling an urgent and unmet clinical need.

No description available.

<p>A multitude of neurologic diseases are increasing in patients that both diminish quality and quantity of life. My dissertation research focused on unraveling the blood-brain barrier’s alterations (BBB), primarily in lung cancer brain metastases, the most common brain metastasis in patients. We optimized a reliable and reproducible mouse model for creating brain metastases using patient derived brain seeking cells of non-small lung cancer (NSCLC) using ultrasound-guided intracardiac injection. I then evaluated brain tissue with qualitative and quantitative immunofluorescence for individual components of the BBB. Using this experimental method, I was able to identify the specific shift of each BBB component over time in NSCLC brain metastases. I then used human brain metastases specimens to demonstrate the clinical relevance of my findings. These results show distinct alterations in the BBB, which have the potential for targeting therapeutic delivery to extend patient survival. I was also able to characterize a novel epithelial-mesenchymal (EMT) phenotype in vertebral metastases of NSCLC in our model, with features similar to those seen in human patients. Most recently, I analyzed patterns of paracellular permeability associated with each BBB component of NSCLC brain metastases which may provide direct passageways for therapeutic delivery. Altogether, this research offered foundational evidence for the future development of targeted novel therapeutics, including nanoparticles. Outside of the brain metastases field, we used an experimental framework to successfully characterize the BBB alterations in a traumatic brain injury model (bTBI). These findings provided the first description of this unique pathology and the framework for developing therapeutics in other neurologic diseases. Although my research work has focused on animal models of disease, future directions based on my research work include the developing a novel 3D BBB-on-chip device to enable high throughput novel therapeutic delivery through the BBB. Long-term, identifying targetable alterations in the restrictive BBB using <i>in vitro</i> and <i>in vivo</i> models provides a potential conduit for effective prevention and treatment of a myriad of neurologic diseases to prolong patient survival and quality of life.</p>

No description available.

Chemoresistance is a major obstacle in successful chemotherapy. This research explored several genetic and epigenetic factors involved in chemoresistance, angiogenesis and metastasis in the human non-small cell lung cancer cell line A549 and its paclitaxel resistant subclone A549-T24. We characterized various morphological and biochemical differences (with a special focus on the Bcl-2 family of apoptotic regulators) between the two cell lines. Although paclitaxel induced apoptosis in both the cell lines, the subclone was 10 fold more resistant to this drug. Our immunocytochemistry data indicated that VEGF (a potent inducer of angiogenesis) and VEGF receptor-2 mRNA expression levels were higher in A549-T24 cells compared to those in A549 cells. We also observed a higher angiogenic potential in A549-T24 cells as determined by the effect of these cells on endothelial cell growth and cell sprouting using EA.hy926 human umbilical vein endothelial cells and rat aortic ring models, respectively. Our data suggested that tumor cell-induced angiogenesis may involve activation of nitric oxide, calcium and PI3K signaling pathways. Intracellular calcium [Ca 2+ ] i plays a critical role in cellular growth and apoptosis. We characterized alterations in the regulatory pathways of [Ca 2+ ] i handling in our cell lines. While the endoplasmic reticulum calcium store ([Ca 2+ ] er ) was significantly lower, calcium influx pathways were considerably inhibited in A549-T24 cells compared to A549 cells. We investigated the actions of 2-aminoethoxydiphenyl borate to release [Ca 2+ ] er and to block store operated Ca 2+ channels. In addition, we studied the role of Ca 2+ in thapsigargin-induced apoptosis in A549 cells. Integrins, a family of cell adhesion proteins, inhibit apoptosis via activation of survival signals. Integrin (mainly β 3 and α 5 ) gene expression patterns and functions differed between A549 and A549-T24 cell lines, suggesting that adhesion to matrix elements may modulate the response to paclitaxel. Indeed, adhesion to extracellular matrix proteins via integrins resulted in a further decrease in chemosensitivity in A549-T24 cells with simultaneous inactivation of BAD (a pro-apoptotic protein). Cell adhesion mediated drug resistance was successfully reversed using integrin blockers (GRGDS and LM609). In summary, our data suggested that chemoresistance is multifactorial. Understanding the molecular mechanisms of chemoresistance will enable the design of better anticancer agents.