) The selective expression in tumor cells of non-human genes that can produce toxic drugs is being considered for the treatment of various solid tumors that are refractory to existing chemotherapeutic agents. We have developed a strategy utilizing the substrate characteristics of E. coli purine nucleoside phosphorylase (PNP) to activate purine nucleoside prodrugs (E. coli PNP recognizes adenine-containing nucleosides as substrates whereas human PNP does not). Our approach has numerous characteristics that distinguish it from the other suicide gene therapy strategies (for example, high bystander activity, potency of the toxic purines generated, activity against non-proliferating tumor cells, potent anti-tumor effects after 1 dose of compound). During the last four years we have progressed from a new in vitro observation to successful demonstration of the feasibility of this approach in animal tumor models. We believe that the unique attributes of the E. coli PNP gene therapy strategy in conjunction with some of the existing vectors could result in significant improvements in antitumor therapy. The long-term objective of this application is to develop this idea into a useful anti-tumor therapy. To reach this objective we have three major goals: 1) to demonstrate the feasibility of this approach in animal tumor models; 2) to create better prodrug/enzyme combinations to improve upon the success that we have had with E. coli PNP; and 3. to generate an increased basic understanding of this strategy. This NCDDG is composed of 4 programs and one core. The objective of the: Molecular Biology Program is to develop procedures to selectively deliver genes into tumor cells of whole animals; Biochemistry Program is to fully characterize the biochemical pharmacology of the purine nucleoside analogs and their respective bases to aid in the rational design of new prodrugs; Chemistry Program is to design and synthesize nontoxic purine nucleoside prodrugs that are cleaved to toxic purines by new enzymes developed in this application; X-ray Crystallography Program is to determine the structure of PNP's to aid in the design of new compounds and enzymes; and Chemotherapy Core is to evaluate the antitumor activity of the prodrugs developed in this NCDDG in relevant animal tumor models developed with the aid of the Molecular Biology Program. The overall NCDDG is therefore intended to capitalize on emerging mechanisms for delivery of genes to pre-existing tumors, exciting preclinical efficacy data, and the discovery of novel enzyme/prodrug combinations.
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