Abstract
Humans with congenital homozygous deficiency of the purine degradative enzyme purine nucleoside Phosphorylase (PNP, E.C. 2.4.2.1) exhibit profound impairment in the T cell, but not B cell, arm of the immune system.1 Because of the importance of PNP in T cell development and/or function, it has been reasoned that PNP inhibitors might provide novel therapy for human disorders in which T cell function is central to the disease pathogenesis. Such an agent would, in theory, be B cell-sparing and relatively selective for replicating T cells, and hence non-inhibitory for quiescent (both memory and naive) T cells. After several years of pursuing this objective, we have identified a novel and highly potent inhibitor of PNP, CI-1000 (PD 141955-2; 2-amino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-one HCl; 9-deaza-9-(3-thienylmethyl)guanine; BCX-5*).2 The Ki of CI-1000 for human erythrocyte PNP is 67 nM,2 while the IC50 using calf spleen PNP is reported to be 80 nM.3 When tested concomitantly with 2’-deoxyguanosine (GdR), CI-1000 potently inhibits 3H-TdR uptake by MOLT-4 and CEM T cell lymphoblasts, but not B cell lymphoblasts,2’4 produces concentration-dependent inhibition of the human mixed lymphocyte reaction (MLR),5 and dose-dependently elevates dGTP both in T lymphoblasts and in the MLR.2, 4, 5 CI-1000 also exerts potent growth inhibition of the human cutaneous T cell lymphoma cell line MyLa via a mechanism that does not appear to involve accumulation of dGTP.6 In rats following oral administration, CI-1000 causes dose-related elevation of plasma nucleosides over the range of 0.5 to 150 mg/kg.2 Plasma inosine levels in rats following a single oral dose of CI-1000 approximate the lower levels found in PNP-deficient children, and persist despite declining CI-1000 concentrations in plasma.1, 2 When added to human or rat whole blood that had been spiked with GdR or inosine (HxR), CI-1000 markedly reduced the rate of purine nucleoside degradation compared with untreated whole blood.7 The studies described here were undertaken to determine the extent of activity of CI-1000 in a comparable system using whole blood from cynomolgus monkeys. Studies in monkeys were prompted by the need to construct an integrated hypothesis incorporating the pharmacokinetiq activity of CI-1000 with pharmacodynamic effect (nucleoside elevation) and toxicologic and immunotoxicologic findings in monkeys, so as to provide a model to assist in the evaluation of CI-1000 in human trials.
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Gilbertsen, R.B., Dong, M.K. (1995). Blockade of Nucleoside Degradation in Monkey Whole Blood in Vitro by CI-1000, a Purine Nucleoside Phosphorylase (PNP) Inhibitor. In: Sahota, A., Taylor, M.W. (eds) Purine and Pyrimidine Metabolism in Man VIII. Advances in Experimental Medicine and Biology, vol 370. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2584-4_37
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DOI: https://doi.org/10.1007/978-1-4615-2584-4_37
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