Purine nucleoside phosphorylase inhibition as a novel therapeutic approach for B-cell lymphoid malignancies

Semin Oncol. 2007 Dec;34(6 Suppl 5):S29-34. doi: 10.1053/j.seminoncol.2007.11.004.

Abstract

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of ribonucleosides and 2'-deoxyribonucleosides to their respective bases. Endogenous PNP deficiency leads to specific T-cell immunodeficiency, a genetic disease that has prompted the development of PNP inhibitors as potential therapies for T-cell-mediated diseases. PNP inhibition leads to the elevation of 2'-deoxyguanosine levels and accumulation of intracellular deoxyguanosine 5'-triphosphate, inducing cellular apoptosis. Forodesine is a highly potent, orally active, rationally designed PNP inhibitor that has shown activity in preclinical studies with malignant cells and clinical utility against T-cell acute lymphoblastic leukemia and cutaneous T-cell lymphoma. Additional preliminary findings support its use for the management of some B-cell malignancies.

Publication types

  • Review

MeSH terms

  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Deoxyguanine Nucleotides / metabolism
  • Humans
  • Leukemia, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Purine Nucleosides / pharmacology*
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Purine-Nucleoside Phosphorylase / drug effects
  • Pyrimidinones / pharmacology*

Substances

  • Deoxyguanine Nucleotides
  • Purine Nucleosides
  • Pyrimidinones
  • forodesine
  • deoxyguanosine triphosphate
  • Purine-Nucleoside Phosphorylase