This Laboratory Program describes use of the E. coli PNP gene for destroying human cancer cells in vitro and in vivo. This will include characterization of a clinically approved prodrug (F-araAMP) that mediates bystander killing, and studies of both safety and efficacy in animal models. We plan to develop vectoring strategies for delivery of PNP, and improve our understanding of enzymatic chemosensitization. This information, together with new molecular tools (monoclonal and polyclonal antibodies against E. coli PNP; purified PNP protein) form the foundation of the three Specific Aims in this application, as described below:
Specific Aim I : Improve the therapeutic usefulness of E. coli PNP prodrugs and examine mechanism of action. We will explore thresholds for bystander killing, ways to overcome toxicity, and spectrum of activity conferred by the strategy in vivo.
Specific Aim II : Develop clinically useful vector systems for delivering E. coli PNP to tumors in vivo. We will: i) refine gamma1 34.5 deleted herpes viral vectors specifically for use with E. coli PNP and ii) improve upon recent data indicating anti-tumor activity with adenovirus encoding E. coli PNP by augmenting activity and intra-tumoral distribution.
Specific Aim III : Validate the E. coli PNP strategy in vivo and test spectrum of activity and safety in murine models of glioma, colon, and head/neck tumors. These experiments are intended to demonstrate tumor regressions and cures in vivo using a potent bystander killing mechanism, establish broad spectrum of activity for the strategy, and provide a foundation for testing the same approach in human subjects in vivo. ? ? ?
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