Journal
EXPERT OPINION ON INVESTIGATIONAL DRUGS
Volume 15, Issue 12, Pages 1601-1613Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/13543784.15.12.1601
Keywords
arabinosylguanine; BCX-1777; forodesine; nelarabine; purine nucleoside; phosphorylase; T-cell lymphoblastic leukaemia/lymphoma
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Funding
- NCI NIH HHS [CA57629] Funding Source: Medline
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Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disorder in which the specific molecular defect was identified. Clinically, a lack of PNP manifests as profound T-cell deficiency with minor or variable changes in the humoral system. Biochemically, the absence of PNP results in an increase in plasma cleoxyguanosine (dGuo) and a T-cell-specific increase in intracellular cleoxyguanosine triphosphate (dGTP). This observation has been the impetus for the search for either inhibitors of the enzyme or PNP-resistant dGuo analogues as potential anti-T-cell-lineage agents over the past 30 years. Forodesine (an inhibitor of PNP) and nelarabine (a PNP-resistant dGuo analogue) proved to be T-cell selective when tested in clinic. This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents.
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