TY - JOUR
T1 - Pharmacology and Mechanism of Action of Forodesine, a T-Cell Targeted Agent
AU - Gandhi, Varsha
AU - Balakrishnan, Kumudha
N1 - Funding Information:
Dr Gandhi has received research grant support, honoraria, and consulting fees from BioCryst Pharmaceuticals.
Funding Information:
This work was supported in part by National Institutes of Health grant nos. CA57629 and CA81534.
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
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U2 - 10.1053/j.seminoncol.2007.11.003
DO - 10.1053/j.seminoncol.2007.11.003
M3 - Article
C2 - 18086347
AN - SCOPUS:37049019677
SN - 0093-7754
VL - 34
SP - S8-S12
JO - Seminars in oncology
JF - Seminars in oncology
IS - SUPPL. 5
ER -