Forodesine

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Abstract

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine-salvage metabolic pathway. A deficiency in PNP is associated with significant T-cell depletion and immune deficiency. Forodesine is a potent PNP inhibitor that was designed based on the transition-state structure stabilized by the enzyme. When PNP is inhibited by forodesine, 2′-deoxyguanosine remains unmetabolized and is transported into cancer cells via nucleoside transporters. Inside the cells, 2′-deoxyguanosine is phosphorylated to deoxyguanosine monophosphate by deoxycytidine kinase and then to deoxyguanosine triphosphate by other kinases. The intracellular deoxyguanosine triphosphate inhibits ribonucleotide reductase, induces deoxyribonucleotide pool imbalance, and inhibits DNA synthesis and repair. In early clinical trials, forodesine demonstrated modest anticancer efficacies. Drug-related adverse events, including lymphocytopenia and neutropenia, were generally tolerable. Forodesine is now being investigated for its clinical efficacy against T-cell malignancies, such as T-cell leukemia and cutaneous T-cell lymphoma.

Keywords

Forodesine Purine nucleoside phosphorylase 2′-deoxyguanosine Deoxyguanosine triphosphate T-cell malignancies 
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Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Hematology and OncologyUniversity of FukuiFukuiJapan
  2. 2.Vice-President, University of FukuiFukuiJapan

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