O carcinoma epidermoide do esôfago continua sendo a principal neoplasia maligna esofágica na população brasileira. Os objetivos desta investigação foram: avaliar a imuno-expressão de um grupo de proteínas relacionadas à via intrínseca da apoptose (bax, APAF-1 e citocromo c) e da proteína p53 em um grupo de carcinomas epidermoides do esôfago; confrontar estes resultados com a atividade proliferativa medida pela imuno-expressão do antígeno Ki67 e com a atividade apoptótica medida pela imuno-expressão da caspase 3 clivada; e confrontá-los com parâmetros implicados no estadiamento do carcinoma epidermoide do esôfago (invasão local ou pT, estado dos linfonodos regionais ou pN, grau de diferenciação do tumor primário e local do tumor primário no esôfago) e com o tamanho do tumor primário. De um grupo inicial de 91 carcinomas esofágicos consecutivos, 66 carcinomas epidermoides do esôfago foram revistos, alocados em micromatrizes teciduais e submetidos à técnica de imuno-peroxidase com anticorpos primários anti: bax, APAF-1, citocromo c, p53, Ki67 e caspase 3 clivada. Suas imuno-expressões foram semiquantificada de 0 a 5+, exceto caspase 3 clivada que foi contada em 1000 células. Apresentaram amostras válidas um conjunto de 63 carcinomas epidermoides do esôfago. A mediana de imuno-expressão destas 6 proteínas foi: 2+, 5+, 5+, 5+, 3+ e 26, respectivamente. Houve correlação positiva entre a imunoexpressão do antígeno Ki67 e a de caspase 3 clivada (coeficiente rho de Spearman =0,373, p=0,003). Houve associação entre a imunoexpressão de APAF-1 e o grau de diferenciação, com valores maiores de APAF-1 para os carcinomas epidermoides do esôfago bem diferenciados (mediana de 5+ para tumores bem diferenciados, contra mediana de 2+ para tumores pouco diferenciados, p<0,001, teste de Kruskal-Wallis). Houve associação entre o tamanho do tumor primário e o nível de invasão local do tumor primário, com tamanhos maiores quanto maior o nível de invasão local dos carcinomas epidermoides do esôfago (mediana de 32,5 mm para os tumores pT1 e mediana de 50,0 mm para os tumores pT3 ou pT4, p=0,027, teste de Kruskal-Wallis). Não houve associação entre as demais variáveis. Embora atividade proliferativa e atividade apoptótica caminhem juntas nos carcinomas epidermoides do esôfago, no estágio invasivo do principal tipo histológico de carcinoma esofágico da população brasileira, não são mais os fatores ligados à via intrínseca da apoptose que influenciam a sua progressão. Além disso, se a imunoexpressão aumentada da proteína APAF-1 estimula a diferenciação nos carcinomas epidermoides esofágicos, não o faz através de estímulo da atividade apoptótica pura e simplesmente / Squamous cell carcinoma of the esophagus remains as the major malignant esophageal neoplasm in the Brazilian population. The objectives of this study were: to assess the immunoexpression of a group of proteins related to the intrinsic pathway of apoptosis (bax, APAF-1 and cytochrome c) and to p53 protein in squamous cell carcinoma of the esophagus; to confront these results with proliferative activity measured by the immunoexpression of Ki67 and with apoptotic activity measured by the immunoexpression of cleaved caspase 3; and to confront them with parameters involved in the staging of squamous cell carcinoma of the esophagus(local invasion or pT, lymph node status or pN, grade of differentiation of primary tumor and site of primary tumor in the esophagus) and with size of primary tumor. From a starting group of 91 consecutive carcinomas of the esophagus, 66 squamous cell carcinomas of the esophagus were selected, revised, placed in tissue microarrays blocks, and submitted to immunoperoxidase technique with primary antibodies to: bax, APAF-1, cytochrome c, p53, Ki67 and cleaved caspase 3. The immunoexpression was semiquantified in a scale from 0 to 5+, except for cleaved caspase 3, whicht was counted in 1000 cells. Sixty three squamous cell carcinomas of the esophagus displayed valid cores for analysis. The median immunoexpression of these 6 proteins were: 2+, 5+, 5+, 5+, 3+ and 26, respectively. A positive correlation was found between Ki67 antigen and cleaved caspase 3 immunoexpression (Spearmans rho coefficient =0.373, p=0.003). There was association between the immunoexpression of APAF-1 and the grade of differentiation, with higher values of APAF-1 for well differentiated squamous cell carcinomas of the esophagus (median of 5+ for well differentiated tumors and median of 2+ for poorly differentiated tumors, p<0.001, Kruskal-Wallis test). The size of primary tumor was statistically associated to the degree of local invasion of primary tumor, with higher size associated to deeper local invasion (median of 32.5 mm for pT1 tumors and median of 50.0 mm for pT3 or pT4 tumors, p=0.027, Kruskal-Wallis test). There was no association among the other variables. Although proliferative activity and apoptotic activity go together in squamous cell carcinomas of the esophagus, the factors involved in the intrinsic pathway of apoptosis does not differ significantly according to the histological parameters in the invasive phase of the development of squamous cell carcinoma of esophagus. Moreover, , if increased immunoexpression of APAF-1 stimulates differentiation of squamous cell carcinomas of the esophagus, it does not work through direct higher apoptotic activity

Abstract Lymphomas are a heterogeneous group of malignancies, which usually have a good prognosis and high cure rates. Lymphomas are sensitive to chemotherapy and radiotherapy, and many patients can be cured even after a relapse, resulting in a need for effective follow-up. However, the cost-benefit ratio of radiological imaging in predicting the forthcoming relapses is poor. Consequently, there is a need for biological prognostic and predictive markers to distinguish patients at the highest risk of relapse at the time of diagnosis or during follow-up. Despite rapid progress in lymphoma treatments, some patients still die from lymphoma. Thus, more data on the basic biological features of lymphomas are also needed. Gelatinases (MMP-2 and MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2) have been found to play a role in the progression of solid tumours. TP53 is a tumour suppressor gene, the mutations and protein over-expression of which have been demonstrated to be associated with survival in most cancer types. There is also some evidence that these proteins could have prognostic significance in lymphomas as well. In the present study, the tissue expression, plasma concentrations and clinical value of gelatinases and their tissue inhibitors were evaluated in lymphomas. 249 primary tissue samples from patients with Hodgkin, follicular, or diffuse large B-cell lymphoma were analysed for expression of gelatinases and/or their inhibitors using immunohistochemistry. In follicular lymphoma, p53 protein expression was also investigated. The plasma samples of 126 lymphoma patients and a control group of 44 healthy volunteers were collected and studied by ELISA. TIMP-1 expression correlated with bulky tumour and nodular sclerosis subtype of Hodgkin lymphoma. In follicular lymphoma, p53 over-expression was an independent adverse prognostic factor for survival and a predictor of histological transformation. Plasma MMP-2-TIMP-2 complex appeared to be a potential follow-up marker predicting the risk of relapse in lymphoma patients. Plasma levels of the MMP-2-TIMP-2 complex, proMMP-2, TIMP-2 and proMMP-2/TIMP-2 ratio were at abnormal levels both in patients with newly diagnosed lymphoma and those in remission compared to healthy controls. The clinical significance of these markers needs further studies.

Amplification and/or overexpression of the Mdm2 oncogene occurs in many human cancers. Mdm2 promotes cellular proliferation, interferes with apoptosis, and induces tumor formation through the negative regulation of the p53 tumor suppressor. More than thirty percent of human tumors overexpressing Mdm2 also present with alternatively spliced Mdm2 isoforms that cannot directly bind p53. The presence of Mdm2 isoforms in tumors correlates with a higher tumor grade and a poorer prognosis for the patient. To investigate the function of Mdm2 isoforms in tumorigenesis, we have isolated a number of Mdm2 splice forms from tumors obtained from Mdm2-transgenic mice and find that the most frequently observed splice form in human tumors, Mdm2-b, is conserved in mice. Although the Mdm2-b protein is incapable of binding to p53 and is unable to localize to the nucleus, we demonstrate that Mdm2-b promotes cell growth in NIH3T3 cells, Rb-deficient, p19-deficient, and p53-deficient primary cells. We also show that Mdm2-b inhibits apoptosis in response to serum withdrawal and restimulation, doxorubicin treatment, and TNF-alpha administration. Mdm2-b induces foci formation in vitro and directly contributes to tumor formation in GFAP-Mdm2 transgenic mice. We propose that Mdm2-b promotes tumor growth by upregulating RelA (P65) protein levels and activity in a p53-independent manner. To better understand additional functions of Mdm2 that are p53-dependent, we have generated an Mdm2 conditional mouse model. Using primary mouse embryonic fibroblasts derived from Mdm2 conditional mice, we demonstrate that p21 is required for p53-dependent apoptosis initiated by Mdm2 loss. In support of this observation, we also note that p21-loss partially rescues embryonic lethality of Mdm2 null mice. We further show that p21-loss partially rescues the embryonic lethality caused by the loss of the Mdm2 family member, Mdm4. We address the possibility that Mdm2 and Mdm4 may play redundant roles during embryonic development and find that Mdm2 overexpression fully rescues the embryonic lethality resulting from Mdm4 loss. Our findings demonstrate that both Mdm2 and Mdm4 play critical roles in modulation of the p53 tumor suppressor pathway and that their deregulation can result in tumor formation through both p53-dependent and independent pathways.

No description available.

Yes / The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed.

Dados recentes do nosso laboratório demonstram que somente a co-transdução, não a tradução individual, com vetores adenovirais portadores de Interferon-beta (IFN?) (citocina imuno modulatória) e p19Arf (parceira funcional da proteína supressora de tumor p53) resulta na morte celular massiva do melanoma murino B16F10. A capacidade desse tratamento combinado de induzir uma resposta imune antitumoral ainda não foi avaliada. Dessa maneira, o objetivo do presente trabalho foi investigar se células B16F0 tratadas por essa combinação são capazes de induzir uma resposta imune antitumoral em um modelo de vacinação profilático de melanoma. Para isso, essas células foram co-transduzidas com os vetores AdPGp19 e AdPGIFN? e 48 horas depois, inoculadas como agente vacinal no flanco esquerdo (sítio da vacina) de camundongos C57BL/6 imunocompetentes. Sete dias após a última vacinação, esses animais foram desafiados com células B16F10 naïve no flanco direito (sítio do desafio). A progressão tumoral do desafio foi significativamente reduzida, mesmo quando o desafio tumoral foi feito 73 dias após da vacinação. Porém, como os animais imunizados desenvolveram tumores no sítio da vacina, condições para o uso dessas células tratadas foram avaliadas, revelando que: o número de células e de aplicações usadas durante a vacinação tem influência no aparecimento desse tumores, e que apenas com o tratamento combinado os camundongos permanecem livres de tumor. A influência do sistema imune para este resultado foi revelada após protocolo de imunussupressão. Em seguida, o papel da p19Arf e do IFN? na proteção antitumoral da combinação foi estudado. In vitro, os efeitos antitumorais da combinação parecem ser mais influentes da reposição de p19Arf do que da expressão de IFN?, mas já in vivo, na presença do sistema imune, foram mais dependentes do IFN?. Com a combinação estes efeitos mostraram-se mais pronunciados, induzindo uma proteção antitumoral e maior sobrevida aos animais vacinados. Estes resultados indicam que a combinação p19Arf e IFN? pode ser aplicada como um agente imunoterápico e sugerem que a associação entre morte celular e imuno estimulação pode beneficiar o tratamento contra o câncer / Previously, we have shown in a mouse melanoma model of in situ gene therapy that co-transduction, but not individual application, with adenovirus vectors expressing the Interferon-beta (IFN?) (immune modulatory cytokine) and p19Arf (functional partner of the p53 tumor suppressor) transgenes results in massive cell death and reduced tumor progression. However, the capability of this combined treatment to stimulate an antitumor immune response has not been evaluated. Therefore, the aim of this work was to investigate, trough a prophylactic vaccine model, if B16F10 cells treated by the p19Arf and IFN? combination could induce such immune response. To do so, these cells were co-transduced by the AdPGp19 e AdPGIFN? adenoviral vectors and 48 hours after, inoculated as a vaccine agent in the left flank (vaccine site) of immune competent C57BL/6 mice. Seven days after the last vaccine, a tumor challenge was done with naïve B16F10 cells in the right flank (challenge site). Tumor progression was markedly reduced, even when challenge was done 73 days after the vaccination. However, since these animals developed tumors where the vaccine was applied, more appropriate conditions for the use of these treated cells were pursued, thus revealing that: the number of cells and inoculations can dictate tumor development, and also, that only with the combined treatment was tumor formation abolished. The influence of the immune system for this result was revelead by performing an immune supression protocol. Next, the roles of p19Arf and of IFN? were studied. In vitro, the antitumor effects were stronger upon the introduction of p19Arf than IFN?, but in vivo, in the presence of the immune system, the effects were more IFN? dependent. In fact, these effects were more pronouced with the combined treatment, inducing protection against tumor formation and progression and increasing survival in the vaccinated animals. Taken together, these results demonstrate the application of cells treated by the p19Arf e IFN? combination as an effective vaccine agent and also indicates that the association between cell death and immune stimulation may benefit the treatment of cancer

O diagnóstico precoce dos Segundos Tumores Primários (STP) em pacientes já tratados por um carcinoma de cabeça e pescoço deve ser realizado, pois possibilita um tratamento resolutivo com baixa morbidade. O objetivo deste trabalho é avaliar se a cromoscopia com Lugol permite uma melhora na identificação de lesões malignas ou pré malignas em fases iniciais na boca e orofaringe, bem como se a imunoexpressão do p53 e da Metalotioneína no tumor índice predizem o aparecimento de um STP. Foi realizado um estudo prospectivo onde dois grupos comparáveis de portadores de carcinoma epidermóide de cabeça e pescoço foram formados (um com 106 pacientes e outro com 105 pacientes). Foram acompanhados durante um período médio de 25 meses aproximadamente. No primeiro grupo (grupo A) não foram utilizados corantes, já no segundo (grupo B) utilizou-se o Lugol. Foi observado um número de diagnósticos 200% maior no grupo em que foi utilizada a coloração de Lugol (grupo B) em relação ao grupo A. A imunoexpressão aumentada do p53 no tumor índice foi estatisticamente significante quando o paciente desenvolveu um segundo tumor primário diagnosticado pelo Lugol, não visível sem o corante, o que não ocorreu com a metalotioneína. / The early diagnosis of seconds primary tumors (STP) in patients already treated for carcinoma of the head and neck should be done, because enables a resolutive treatment with low morbidity. The objective of this paper is to evaluate whether chromoscopia using Lugols solution allows an improvement in the identification of malignant or pre malignant lesions in early stages in the mouth and oropharynx, and whether the expression of P53 and metallothionein in tumor index predict the emergence of a STP. A prospective study was conducted, where two groups statistically similar of patients with head and neck squamous cell carcinoma (one with 106 patients and another with 105 patients) were followed-up for a median period of 25 months, approximately. In the first group dyes were not used, and in the second Lugols solution was employed. It was observed a number of diagnoses 100%i higher in the group that Lugols solution was used. The increasing of P53 expression in tumor index was statistically significant when the patient developed a second primary tumor diagnosed by Lugol, not visible without dye, which has not occurred with metallothionein.

Introdução: Adenocarcinomas gástricos múltiplos primários (AGMP) são encontrados em 3,5% a 10% de todos os pacientes com câncer gástrico. A multiplicidade tumoral é amplamente reconhecida como indicador de predisposição genética para o desenvolvimento de neoplasias Além disso, as rotas de carcinogênese não estão claramente definidas nestes tumores (rota mutadora, ou supressora, ou da E-caderina). Objetivo: avaliar a imunoexpressão de hMLH1, hMSH2, e hMSH6 (rota mutadora), p53 (rota supressora) e E-caderina nos AGMP comparando-se com adenocarcinomas únicos (pareados quanto ao sexo, idade, tipo histológico, localização e estádio) e sua relação com dados clínico-patológicos. Casuística: dezenove pacientes com AGMP foram comparados a 21 pacientes com tumores gástricos únicos quanto a características imunohistoquímicas. Métodos: Blocos de tecido fixados em formalina a 10% e incluídos em parafina foram submetidos a cortes histológicos de 4 mm, para as avaliações histológica e imunohistoquímica para hMLH1, hMSH2, hMSH6, p53 e E-caderina. Resultados: A média de idade dos pacientes com AGPM foi de 66 + 9,06 anos, e de 60 + 16,9 anos nos pacientes com tumor único (P=0,56). Vinte e dois tumores estavam localizados na porção distal do estômago; 14, no corpo e cinco na porção proximal. Em 14 pacientes, as lesões eram próximas (< 3 cm), enquanto que, em cinco pacientes, as lesões estavam em outra porção do estômago. O estágio final anatomopatológico pós-operatório foi: 15 no estágio T1 (37,5%) (8 múltiplos e 7 únicos), 7 no estágio T2 (17,5%) (1 múltiplo e 6 únicos), 17 no estágio T3 (42,5%) (9 múltiplos e 8 únicos) e 1 no estágio T4 (27,5%) (1 múltiplo). Segundo a classificação de Laurén, 45 dos tumores foram do tipo intestinal (29 múltiplos e 16 únicos), 16 do tipo gástrico (12 múltiplos e 4 únicos) e um tumor do tipo misto (1 único). O estádio anatomopatológico revelou 30 tumores avançados (16 múltiplos e 14 únicos) e 32 precoces (25 múltiplos e 7 únicos). Na imunohistoquímica, não houve diferença entre a imunoexpressão nos dois grupos de tumores quanto a: hMLH1 (24,3% vs. 19% P=0,64), hMSH6 (4,8% vs. 2,4%, P=0,68), p53 (39% vs. 24%, P=0,35) e E-caderina (27% vs. 19%, P=0,46). hMSH2 foi positivo em todos os casos. Não houve associação entre os imuno-marcadores e os dados clínico-patológicos. Conclusões: 1. As rotas de carcinogênese, mutatora, supressora e E-caderina parecem estar independentemente envolvidas no desenvolvimento dos AGMP; 2. Não houve diferença de imunoexpressão dos marcadores analisados quando compararam-se os AGMP e os tumores únicos. / Introduction: Multiple primary gastric adenocarcinomas (MPGA) have been reported from 3.5% to 10% of all patients with gastric cancer. Tumoral multiplicity is largely known as an indicator of genetic predisposition for the development of neoplasias. Moreover, the route of carcinogenesis has not been clearly clarified in these tumors (mutator pathway or suppressor pathway). Aim: to evaluate the immunoexpression of hMLH1, hMSH2, and hMSH6 (mutator pathway), p53 (suppressor pathway) and E-cadherin in the MPGA, comparing to solitary adenocarcinomas (similar gender, age, histological type, location and staging) and also the relation to the clinicopathological data.: Casuistics: Nineteen patients (Group 1) with MPGA were compared to 21 patients (Group 2) with solitary gastric tumors regarding clinicopathological characteristics and immunohistochemistry. Methods: Blocks of tissue fixed in 10% formalin and embedded in parafin were submitted to 4 mm sections for histological and immunohistochemistry analysis for hMLH1, hMSH2 and hMSH6 (mutator pathway), p53 (suppressor pathway) and E-cadherin. Results: The mean age for the MPGA was 66.8 + 9.06 years, and 59.0 + 16.9 years for the solitary tumor group(P = 0.27). Twenty-two tumors were in the distal stomach, 14 were in the body and five in the proximal portion. In 14 patients the lesions were close to each other (< 3 cm), while in five patients the neoplasias were distant, in another portion of the stomach.The final postoperative pathological stage was: T1 in 15 (eight multiple and seven solitary), T2 in seven (one multiple and six soliatry), T3 in 17 ( nine multiple and eight solitary) and T4 in one ( one multiple). According to the Laurén classification, 45 tumors were intestinal type (29 multiple and 16 solitary), 16 were diffuse (12 multiple and four solitart) and one mixed type ( one solitary). 30 tumors were diagnosed in advanced staging (16 multiple and 14 soliatry) and 32 were early (25 multiple and seven solitary). There was no difference between the hMLH1 immunoexpression in the two groups (24.3% vs. 19%, P=0.64), hMSH6 (4.8% vs. 2.4%, P=0.68), p53 (39% vs. 24%, P=0.35) and E-cadherin (27% v.s 19%, P=0.46). Immunostaining for hMSH2 was positive in all MPGA, indicating absence of alterations of this repair gene marker. There was no association between the immunomarkers and the clinicopathological data. Conclusions: 1. Routes of carcinogenesis, mutator, suppressor, and E-cadherin appear to be involved independently in the development of MPGA; 2. There was no difference in the markers immunoexpression in the two groups.

O líquen escleroso vulvar é uma doença crônica e benigna, porém apresenta um potencial de malignização para o carcinoma de células escamosas de vulva. Foram estudadas trinta doentes com líquen escleroso vulvar, divididas em três grupos, que fizeram uso tópico de propionato de clobetasol a 0,05%, testosterona a 2% e um placebo, para avaliar a evolução dos sintomas e o comportamento das células marcadas com o anticorpo Ki-67 e a proteína p53 antes e após os tratamentos. Observou-se melhora dos sintomas clínicos com o uso do clobetasol e da testosterona, que foi estatisticamente superior ao placebo (p<0,01). Observou-se diminuição significante das células marcadas com Ki-67 após o tratamento das doentes com o clobetasol (p<0,01) e com a testosterona (p<0,02). Enquanto, nas doentes que utilizaram placebo, observou-se um aumento do Ki-67. Em relação à análise das células marcadas com a proteína p53 também observou-se diminuição significante após o tratamento com o clobetasol (p<0,01) e com a testosterona (p<0,01). Enquanto no grupo placebo observou-se um aumento do p53. Quando se compara a variação do p53 entre os grupos clobetasol, testosterona e placebo observou-se uma diminuição do p53 estatisticamente superior (p<0,001) nas doentes que utilizaram clobetasol. Assim, os resultados mostram uma redução dos marcadores celulares após os tratamentos, e com o p53 a diminuição foi estatisticamente maior no grupo que utilizou clobetasol, sugerindo a eficácia desse tratamento / Vulvar Lichen Sclerosus consists of a benign chronic disease, however featuring a malignant potential for vulvar squamous cell carcinoma. The present study targeted 30 patients diagnosed Vulvar Lichen Sclerosus, divided in three groups, and who made topical use of clobetasol propionate at 0.05%, testosterone at 2% and a placebo, so as to assess the evolution of the symptoms and the behavior of the cells marked with antibody Ki-67 and protein p53, before and after the treatments. The administration of clobetasol and testosterone has proven effective in the management of the clinical symptoms, which turned out to be statistically higher than the placebo (p<0.01). The number of cells marked with Ki-67 decreased significantly patients treated with clobetasol (p<0.01) and testosterone (p<0.02), while the number of such cells increased in those patients who made use of the placebo. The number of cells marked with protein p53 also decreased significantly after the treatment with clobetasol (p<0.01) and testosterone (p<0.01), whereas the placebo group revealed an increased p53. When comparing the decrease of the p53 in the clobetasol, testosterone and placebo groups, we noted a decrease of the p53 statistically higher (p<0.001) in patients under clobetasol; suggesting a reduction in the cellular markers after the treatment. As for the p53, the decrease was statistically higher in the group under clobetasol, suggesting the efficacy of the treatment.

Os avanços científicos das últimas décadas permitiram que a compreensão do câncer evoluísse de uma visão simplista, na qual o principal motor seria uma atividade celular hiperploriferativa, para uma visão mais complexa onde o estado fisiológico geral permite a gênese e progressão tumoral. Essa evolução permite o desenvolvimento de novas abordagens terapêuticas e traz novas esperanças para o tratamento de muitos tipos de cânceres ainda extremamente deletérios. Dentro desse novo panorama, terapias que estimulem a imunidade antitumoral têm se mostrado extremamente promissoras. Nesse trabalho, procuramos investigar os efeitos antitumorais desencadeados pela combinação da indução de morte celular e imunoestimulação. Para tanto, visamos à recuperação da via de p53 (pela transferência gênica do próprio p53 ou p19) associada à transferência gênica de IFNbeta. A transferência gênica foi mediada por vetores adenovirais do sorotipo 5. Nossas observações, em um modelo murino de carcinoma pulmonar, permitem concluir que esta linhagem é sensível a morte induzida pela transferência gênica de p19 e não p53. Porém, a transferência gênica intratumoral de IFNbeta se mostrou chave no controle do crescimento do tumor primário. Destacamos, entretanto, que a associação de IFNbeta com p19 produziu efeitos imunoprotetores superiores à transferência de IFNbeta ou p19 sozinhos. Tal efeito parece ser dependente da indução de fatores quimiotáxicos e conseqüente recrutamento de neutrófilos para o sítio tumoral. O efeito da transferência gênica combinada de ambos os genes IFNbeta e p19 se mostrou ainda mais promissor quando associado à cisplatina, induzindo uma notável redução no crescimento tumoral / Scientific advances from the last decades enabled the evolution of our knowledge of cancer from a simplistic vision, in which the main motor was an excessive cell proliferation, to a more complex one, where the general physiologic state enables tumorigenesis and tumor progression. This evolution enabled the development of new therapies and brings new hopes for the treatment of several types of cancers. In this context, therapies that induce an antitumor immunity are very promising. In this work, we are investigating the antitumor effects triggered by the combination of cell death induction and immunostimulation. To this end, we aimed to restore p53 pathway (by p53 or p19 gene transfer) associated with immunostimulation by IFNbeta gene transfer. The gene transfer was mediated by Adenovectors Serotype 5. Our observations in a murine model of lung cancer showed that this cell line is sensitive to cell death induced by p19 gene transfer, but not p53. Nevertheless, intratumoral gene transfer of IFNbeta, was crucial in controlling tumor growth. Moreover, p19 and IFNbeta association induced higher immunoprotecting effects than p19 or IFNbeta alone. This effect seems to be depending on the induction of chemotactic factors, and the recruitment of neutrophils to the tumor site. The effect of combined gene transfer of p19 and IFNbeta was even more promising when associated with Cisplatine, inducing a remarkable reduction in tumor growth