PNP represents an attractive target for drug development based on the profound, selective impairment of T-cell function seen in individuals with an inherited deficiency of PNP. Forodesine, a potent, specific transition-state analog inhibitor of PNP, is currently being investigated for safety and efficacy in T-cell and other malignancies. In a phase I/II single-center, intrapatient dose-escalation study, forodesine (starting dose: 40 mg/m2) was given to 5 patients with relapsed/refractory, aggressive T-cell leukemia/ lymphoma via a 30-min IV infusion, followed 24 hrs later by doses administered every 12 hrs for a total of 9 doses; courses could be repeated every 3–4 weeks, as required. Two patients with refractory T-cell prolymphocytic leukemia (T-PLL) and two patients with T-cell acute lymphoblastic leukemia (T-ALL) showed a decrease in leukemic or prolymphocytic counts in peripheral blood and/or bone marrow. All responders had increases in plasma 2′-deoxyguanosine (dGuo) (Cmax: 2.9 to 34 μM; baseline concentration: 90% to near-normal levels. However, the contribution of a single dose of dexamethasone (40 mg IV given on Day 3) to the reduction in WBC count and blast cells is unknown. This patient’s peripheral blood hematologic profile (WBC, absolute neutrophil, platelet counts and hemoglobin level) returned to near-normal, indicating a specificity of forodesine for leukemic cell populations and supporting that forodesine is an important breakthrough in the development of less toxic ALL therapy. Additional phase II results will be presented. ![Figure][1] Figure [1]: pending:yes
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Isola et al. (2004) studied this question.