Purine nucleoside phosphorylase inhibitors in T-cell malignancies.
Purine nucleoside phosphorylase (PNP)-deficient children exhibit profound impairment in the T-cell component of their immune systems, but have normal B-cell function. This rare condition provides a model for the development of specific inhibitors of PNP, which should enable selective suppression of T-cell function that may be useful in the treatment of T-cell-mediated diseases. BCX-1777 (BioCryst Pharmaceuticals Inc) is a rationally designed, potent transition-state analog inhibitor of PNP. This review provides a summary of in vitro and in vivo inhibition studies of T-cells by BCX-1777, and the role in this process of plasma deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate (dGTP). Preliminary data from a phase I clinical trial of BCX-1777 in patients with T-cell malignancy demonstrated antileukemic activity which can be correlated to an increase in plasma dGuo and intracellular dGTP. This is consistent with results observed in cell cultures, animal studies and PNP-deficient patients. Clinical trials with BCX-1777 have demonstrated that inhibition of PNP leads to T-cell-selective suppression, confirming PNP to be a promising target for the treatment of T-cell-mediated diseases.
Bantia
Shanta
S
BioCryst Pharmaceuticals Inc, Birmingham, AL 35244, USA. sbantia@biocryst.com
Kilpatrick
John Michael
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase