Malignant mesothelioma is an example of a solid tumor extremely unresponsive to conventional therapy, with few patients surviving for more than 12 months regardless of treatment. We postulate that this treatment unresponsiveness is due to apoptosis resistance. BCL-XL is an anti-apoptotic member of the BCL-2 protein family, and is over-expressed in mesothelioma. Attenuated expression of other anti-apoptotic proteins and normal pro-apoptotic protein expression is noted in this tumor. Data from our laboratory suggests that constitutive transcriptional activation of the bcl-xl gene is responsible for protein over-expression. We have demonstrated bcl-xl down-regulation in human mesothelioma cells at the protein and mRNA level by both antisense oligonucleotide and full-length adenoviral antisense constructs leads to apoptotic human cell death in vitro. Down-regulation of bcl-xl also sensitizes mesothelioma cells to subsequent in vitro chemotherapy exposure leading to additive or synergistic cellular death. Pilot studies evaluating in vivo down-regulation of bcl-xl utilizing an adenoviral vector antisense construct or antisense oligonucleotides demonstrate inhibition of mesothelioma tumor growth. These experimental results suggest the following hypotheses: (1) bcl-xl expression is abnormal in mesothelioma due to up-regulation of constitutive transcriptional activity, (2) bcl-xl over-expression is in part responsible for mesothelioma clinical treatment resistance, (3) down-regulation of bcl-xl expression will lead to a bcl-2 family protein """"""""imbalance"""""""" favoring apoptosis, (4) in vivo administration of bcl-xl antisense oligonucleotides will lead to BCL-XL down-regulation and apoptotic death of mesothelioma tumor cells, and (5) down-regulation of BCL-XL expression in vivo will sensitize mesothelioma tumor cells to conventional treatments such as chemotherapy and ionizing radiation. We will test the hypotheses regarding constitutive transcriptional activation by evaluation of the known transcriptional pathways and promoter function for bcl-xl. In vivo treatment hypotheses will be tested by use of established animal xenograft treatment models of mesothelioma. Our goals are to understand the mechanism of transcriptional up-regulation of the bcl-xl gene in this tumor, and to find a more effective clinical treatment for malignant mesothelioma. A more complete knowledge of bcl-xl constitutive up-regulation mechanisms could be of therapeutic import for a number of solid tumors that have a similar bcl-2 family phenotype. Upstream targets regulating bcl-xl expression for use in future therapeutic paradigms may be identified.
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