E coli PNPPurine Analogs

The E. coli purine nucleoside phosphorylase (PNP) is involved in purine metabolism and causes cell death in the presence of nucleoside prodrugs. The prodrugs used with this strategy are 6-methyl purine-deoxyribose (6-MeP-dR), fluoro-deoxyadenosine (F-dAdo), and fluoro-arabinosyl adenosine monophosphate (F-araAMP). E. coli PNP cleaves these prodrugs to methyl purine (6-MeP) and 2-fluoro-adenine (2-F-Ade), respectively (see Fig. 23.7). These two agents are converted to ATP analogs, which inhibit RNA and/or protein synthesis. The specific mechanism of action of these two agents is not known. It is possible that these agents inhibit dsRNA deaminases. However, RNA and/or protein synthesis inhibition makes these agents effective against proliferating and nonproliferating tumor cells [61]. Furthermore, the active metabolites have a high potency and a high bystander activity which does not require cell-to-cell contact, thereby distributing by passive diffusion [62]. Only a few (0.1-1 per cent) expressing cells are needed to kill

FIGURE 23.6 Carboxylesterase (CE).
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