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Gregório JC. Effect of the simultaneous replacement of p16 and p53 genes mediated by a bicistronic adenovirus Adp16IRESp53 in a human lung carcinoma model [Thesis] São Paulo: Instituto de Ciências Biomédicas da Universidade de São Paulo; 2008. This work presents the construction, production and functional evaluation in vitro and in vivo of the bicistronic adenoviral vector Ap16IRESp53 as well as the monocistronic vectors Adp16 and Adp53 in a lung cancer model. The p16 and p53 genes are strong tumor suppressors that act in different pathways of cell cycle control. Considering that several mutation events are involved in tumorigenesis, comes the idea that a greater efficiency in cancer treatment would be reached with delivery of multiples genes. The principal cell line used in this experimental model was H358, derived from human pulmonary carcinoma. The cell line A549, derived from human pulmonary carcinoma, also has been used in our study. Each of these lines present distinct mutational profiles. Our data demonstrate a strong cell death effect in H358 cells transduced with Adp16IRESp53 when compared with Adp16, Adp53 or the reporter AdeGFP and/or AdLacZ. In addition, the bicistronic vector showed a superior effect in cell death than Ap16 and Adp53 delivery in co-transduction assays. In this work, we have also begun to trace a transcriptional profile of genes correlated with cell cycle control of H358 cells post-transduction with bicistronic adenovirus Adp16IRESp53. Real-time PCR demonstrated that p16 and p53 transgenes are expressed more efficiency in the bicistronic configuration than in the Adp16 and Adp53 monocistronics. We have observed that p21 and pro-apoptotic Bax genes are more expressed in the Adp16IRESp53-transduced cells. In contrast, expression of FoxO and the antiapoptotic survivin (SVV) genes were especially reduced in the cells that received Adp16IRESp53. For the in vivo studies, we have used H358 cells implanted subcutaneously in athymic Balb/c nude mice. Our data show significant suppression of tumors treated with the therapeutic adenoviral vectors. In conclusion, the simultaneous replacement of p16 and p53, mediated by the bicistronic vector, may prove to be a promising strategy for gene therapy of lung cancer.

Estudo do efeito da remediação simultânea dos genes p16&lt;sup&gt;INK4a&lt;/sup&gt; e p53 mediada pelo adenovírus bicistrônico Adp16IRESp53 em um modelo de carcinoma de pulmão humano.