Evidence for a Pathway Independent from 2'-Deoxyguanosine and Reversible by IL-2 by which Purine Nucleoside Phosphorylase Inhibitors Block T-Cell Proliferation

Patients with homozygous deficiency of purine nucleoside phosphorylase (PNP) present with a T-cell selective immune deficiency. To elucidate the potential use of PNP inhibitors in the therapy of cutaneous T-cell lymphomas (CTCLs) the authors studied the effects of CI-1000 (formerly PD 141955-2) and CI-972 on a T-cell line My La established from a patient with mycosis fungoides. Both PNP inhibitors had significant, dose-dependent, inhibitory effects on the proliferation of the T-cell line. CI-1000 (ED₅₀: 3.7 μM) was approximately six-fold more potent in blocking ³H-thymidine uptake than CI-972 (ED₅₀: 22.5 μM). The inhibitory effect of either substance could not be increased by addition of deoxyguanosine. Flow cytometric analysis revealed that both PNP inhibitors caused a block in the S-phase of the cell cycle. The inhibitory effect on proliferation was reversible partially by addition of IL-2. When testing proliferation inhibition of both substances on an IL-2-dependent T-cell line (SeAx), their inhibitory effects were reduced significantly. These data document a mechanism of action of the PNP inhibitors independent of deoxyguanosine and partially reversible by IL-2. The authors' observations suggest the potential use of PNP inhibitors in the therapy of cutaneous T-cell lymphomas and provide evidence for a pathway independent from deoxyguanosine by which PNP inhibitors might function in T cells.