Alveolar rhabdomyosarcoma, an aggressive childhood tumor derived from skeletal muscle, exhibits a characteristic 2;13 chromosomal translocation that results in the aberrant expression of a novel fusion protein. The function of the hybrid pax3/ALV protein is unknown but it is thought to act as a transcription factor. To understand the biological significance of this peptide and to determine whether the transcript provides a target for tumor-specific gene modulation, ribozyme-mediated cleavage of the mRNA will be accomplished. Since overexpression of pax3 results in oncogenic transformation in cultured cells, the chimeric pax3/ALV protein may play an important role in both the development of alveolar rhabdomyosarcoma and the inhibition of normal myogenic differentiation. If modulation of the rhabdomyosarcoma phenotype can be achieved, the potential exists for the design of viral vectors that specifically cleave the chimeric mRNA in vivo. Novel adenovirus vectors will be constructed to specifically express ribozymes or suicide inactivation genes in rhabdomyosarcoma. To increase the efficiency of infection of tumor cells in vivo by these recombinant virus, replication-competent adenovirus containing a tumor specific promoter will be produced. The goals of this proposal are therefore to 1) modulate the rhabdomyosarcoma phenotype using ribozymes, 2) design and construct vectors to specifically deliver these agents to the appropriate cells in vivo and 3) develop antibodies raised against the fusion protein to allow rapid diagnosis of alveolar rhabdomyosarcoma in tumor biopsies. Since the use of ribozymes to modulate gene expression is not limited to rhabdomyosarcoma, this proposal may further provide information concerning the applicability of these agents in other tumor model systems.
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