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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4253-4260.
Prepublished online as a Blood First Edition Paper on August 30, 2005; DOI 10.1182/blood-2005-03-1309.
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NEOPLASIA
A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)
Varsha Gandhi,
John M. Kilpatrick,
William Plunkett,
Mary Ayres,
Leigh Harman,
Min Du,
Shanta Bantia,
Jan Davisson,
William G. Wierda,
Stefan Faderl,
Hagop Kantarjian, and
Deborah Thomas
From the Departments of Experimental Therapeutics and Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX; and BioCryst Pharmaceuticals, Inc, Birmingham, AL.
The discovery of purine nucleoside phosphorylase (PNP) deficiency and T lymphocytopenia suggested that inhibition of this enzyme could serve as a therapeutic target. Inhibitors of PNP failed until structure-based synthesis of immucillin-H (BCX-1777, forodesine), a transition-state analog of PNP. The picomolar potency for PNP, T cell-selective cytotoxicity, and animal studies provided the rationale for use of forodesine in T-cell malignancies. Five patients were treated with an intravenous infusion of forodesine (40 mg/m2) on day 1; treatment continued on day 2; forodesine was administered every 12 hours for an additional 8 doses. Plasma and cellular pharmacokinetics and pharmaco-dynamics were investigated. Median peak level of forodesine (5.4 µM) was achieved at the end of infusion. This level was sufficient to increase plasma 2'-deoxyguanosine (dGuo) concentrations in all patients. Intracellular deoxyguanosine triphosphate (dGTP) increased by 2- to 40-fold in 4 of 5 patients (8 of 9 courses) and correlated with antileukemia activity in 4 patients. However, objective responses were not observed. This was the first clinical study in humans to demonstrate the plasma pharmacokinetics and the pharmacodynamic effectiveness of the PNP inhibitor, forodesine; however, regrowth of leukemia cells in the blood and marrow after course 1 suggested that a different therapeutic schedule should be considered for future studies.
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