Purine nucleoside phosphorylase inhibition as a novel therapeutic approach for B-cell lymphoid malignancies.
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.
Furman
Richard R
RR
CLL Research Center, Weill Cornell Medical Center, New York, NY 10021, USA.
Hoelzer
Dieter
D
D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D011684:Purine Nucleosides / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011744:Pyrimidinones / Q000494:pharmacology*
D003848:Deoxyguanine Nucleotides; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase