Document Detail

Purine nucleoside phosphorylase inhibitors in T-cell malignancies.
MedLine Citation:
PMID:  15603259     Owner:  NLM     Status:  MEDLINE    
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.
Shanta Bantia; John Michael Kilpatrick
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Current opinion in drug discovery & development     Volume:  7     ISSN:  1367-6733     ISO Abbreviation:  Curr Opin Drug Discov Devel     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-12-17     Completed Date:  2005-02-04     Revised Date:  2005-11-16    
Medline Journal Info:
Nlm Unique ID:  100887519     Medline TA:  Curr Opin Drug Discov Devel     Country:  England    
Other Details:
Languages:  eng     Pagination:  243-7     Citation Subset:  IM    
BioCryst Pharmaceuticals Inc, Birmingham, AL 35244, USA.
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MeSH Terms
Antineoplastic Agents / therapeutic use*
Cell Proliferation / drug effects
Enzyme Inhibitors / therapeutic use*
Leukemia, T-Cell / drug therapy*,  enzymology,  immunology
Lymphoma, T-Cell / drug therapy*,  enzymology,  immunology
Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
T-Lymphocytes / drug effects,  immunology
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; EC Phosphorylase

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