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 PD141955-2) and
CI-972 on a T-cell line MyLa 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 microM) was approximately six-fold more potent in blocking 3H-thymidine uptake than
CI-972 (ED50: 22.5 microM). 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.