Overexpression of the c-myc oncogene occurs in numerous human tumors including colon, breast, cervix and brain. Whilst clinically useful drugs that specifically interact with the c-myc protein have not been identified, this proposal describes an approach to address tumor-specific therapy based on the function of c-myc as a transcription factor. The hypothesis to be tested is that the selective induction of transcription by c-myc of a carboxylesterase gene can be exploited to produce selective cytotoxicity when tumor cells are exposed to the topoisomerase I inhibitor CPT-11. The rationale for this hypothesis is based upon the observation that carboxylesterases convert the prodrug CPT-11 to its active metabolite SN-38. Specifically, we propose to test whether endogenous overexpression of cmyc in tumor cells can selectively transactivate the c-myc-responsive ornithine decarboxylase promoter allowing transcription of a carboxylesterase. When tumor cells overexpressing c-myc, and therefore the carboxylesterase, are exposed to CPT-11, the drug will be converted to SN-38 and produce tumor-selective cell kill. The feasibility of this approach will be tested in cell lines derived from human tumors and in a preclinical xenograft model of minimal residual disease. The goals of this proposal are therefore: 1) to determine whether tumor-specific expression of target genes can be achieved in cells overexpressing c-myc; 2) to identify a carboxylesterase that can efficiently convert CPT-11 to SN-38; 3) to selectively express this carboxylesterase in tumor cells thereby conferring sensitivity to CPT-11; and, 4) to determine the validity of an approach using adenoviral-mediated delivery of carboxylesterase in combination with CPT-11 to eradicate tumor cells in a minimal residual disease model.
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