Pharmacology and mechanism of action of forodesine, a T-cell targeted agent.
Purine nucleoside phosphorylase (PNP) was recognized more than 30 years ago as a potential target for the treatment of patients with T-cell malignancies when an inherited deficiency of PNP was reported to be associated with a profound T-cell lymphopenia. The biochemical basis for this T-cell deficiency was subsequently shown to be related to the accumulation of plasma 2'-deoxyguanosine (dGuo) and intracellular dGuo triphosphate (dGTP). These observations have led to a search for PNP inhibitors that would be useful clinically in the management of T cell-derived malignancies. The most potent inhibitor of PNP described to date is forodesine, a rationally designed, transition-state analogue inhibitor. The preclinical and clinical pharmacology of forodesine showed its effectiveness in inhibiting PNP and augmenting dGuo levels in plasma. Increased dGTP concentrations in leukemia cells of different lineages provides strong support for the potential use of this agent in the treatment of patients with hematologic malignancies of both T- and B-cell origin.
Gandhi
Varsha
V
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. vgandhi@mdanderson.org
Balakrishnan
Kumudha
K
D053898:Biosynthetic Pathways / Q000187:drug effects; D002986:Clinical Trials as Topic; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy; D011684:Purine Nucleosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*
D003848:Deoxyguanine Nucleotides; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine