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-cel l lymphomas (CTCLs) the authors studied the effects of CI-1000 (former ly PD 141955-2) and CI-972 on a T-cell line MyLa established from a pa tient with mycosis fungoides. Both PNP inhibitors had significant, dos e-dependent, inhibitory effects on the proliferation of the T-cell lin e. CI-1000 (ED(50): 3.7 mu M) was approximately six-fold more potent i n blocking H-3-thymidine uptake than CI-972 (ED(50): 22.5 mu M). The i nhibitory effect of either substance could not be increased by additio n of deoxyguanosine. Flow cytometric analysis revealed that both PNP i nhibitors caused a block in the S-phase of the cell cycle. The inhibit ory 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 in hibitors independent of deoxyguanosine and partially reversible by IL- 2. The authors' observations suggest the potential use of PNP inhibito rs in the therapy of cutaneous T-cell lymphomas and provide evidence f or a pathway independent from deoxyguanosine by which PNP inhibitors m ight function in T cells.