BIOCHEMISTRY OF PURINE NUCLEOSIDE ANALOGS ACTIVATED BY E COLI PNP

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The goal of this NCDDG is to develop a cancer treatment strategy based on the selective expression of E. coli PNP in tumor cells. One of the major objectives of the Biochemistry Program in this NCDDG is to fully characterize the biochemical pharmacology of purine nucleoside analogs that can be used as prodrugs. This program will interact with the Chemistry and X-ray Crystallography Programs in the rational design of purine nucleoside analogs that can be selectively activated by E. coli PNP. In these studies the utilization of the various prodrugs by E. coli PNP and human enzymes that are likely to metabolize purine nucleosides will be determined, and the metabolism of prodrug in whole animals and cell culture will be characterized. These studies are necessary to identify the primary enzyme responsible for creating toxic metabolites of the prodrug. This information will aid in the rational development of less toxic prodrugs that can still be cleaved by E. coli PNP. Another major objective of this program is to determine the activity of E. coli PNP in the various tumor models that will be developed in the Molecular Biology Program and to fully characterize the interaction of the prodrugs with these tumors. This information is necessary to adequately interpret the results of the experiments that measure the efficacy of various prodrugs against tumors that express E. coli PNP. In addition, the mechanisms of action of many of the toxic purines that will be produced by E. coli PNP are poorly understood, and it will be the one of the goals of this program to determine their mechanisms of action so that we may understand how they differ from conventional therapy. Together these studies will support the goals of the NCDDG by supplying the biochemical information that is necessary for the rational development of this strategy for the treatment of cancer.