ABSTRACT
Forodesine is a new and potent purine nucleoside phosphorylase (PNP) inhibitor. Patients with chronic lymphocytic leukemia (CLL) with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200 mg/d) for up to 24 weeks. Eight patients with median lymphocyte count of 35.9 x 10(9)/L and median serum beta2 microglobulin level of 6.45 mg/L were treated. Six had Rai stage III to IV and were previously heavily treated (median prior therapy = 5). Two had transient decrease in lymphocyte count to normal, whereas in 5, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged from 200 to 1300 nM and did not reach desired 2 microM level. PNP inhibition ranged from 57% to 89% and steady-state 2'-deoxyguanosine (dGuo) concentration median was 1.8 microM. Intracellular deoxyguanosine triphosphate (dGTP) increase was very modest, from median of 6 microM to 10 microM. Compared with in vivo, in vitro incubations of CLL lymphocytes with 10 or 20 microM dGuo and forodesine (2 microM) resulted in accumulation of higher levels of dGTP (40-250 microM) which resulted in increase in apoptosis. Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population.
Subject(s)
Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Purine Nucleosides/administration & dosage , Purine Nucleosides/pharmacokinetics , Pyrimidinones/administration & dosage , Pyrimidinones/pharmacokinetics , Vidarabine/analogs & derivatives , Administration, Oral , Aged , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Drug Administration Schedule , Drug Therapy, Combination , Enzyme Inhibitors/blood , Female , Follow-Up Studies , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lymphocyte Count , Lymphocytes/cytology , Lymphocytes/drug effects , Male , Middle Aged , Phosphoric Monoester Hydrolases/metabolism , Purine Nucleosides/blood , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Purine-Nucleoside Phosphorylase/metabolism , Pyrimidinones/blood , Severity of Illness Index , Vidarabine/administration & dosageABSTRACT
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.