Effects of a novel purine nucleoside phosphorylase inhibitor, BCX-34, on activation and proliferation of normal human lymphoid cells

Abstract

The antiproliferative effect of BCX-34 was tested in normal human peripheral blood mononuclear cells (PBMCs) induced to proliferate with OKT3, tetanus toxoid, the mixed lymphocyte reaction, or IL-2. In the case of OKT3, tetanus toxoid, or the MLR the IC50s ranged between 0.7 and 4 μM. With IL-2, the IC50 was 14.6 μM. In T-cells purified by rosetting the IC50 with IL-2 was 0.62 μM. In CD4 or CD8 cells obtained by magnetic activated cell sorting the IC50s with IL-2 were 0.24 and 0.62 μM, respectively. BCX-34 inhibition of proliferation in human PBMCs may not depend entirely upon the accumulation of intracellular dGTP because tetanus toxoid-induced proliferation was inhibited in the absence of deoxyguanosine and was not reversed by deoxycytidine. BCX-34 did not inhibit IL-2 release from PBMCs and did not alter PBMC viability. The results of these studies show that BCX-34 is a potent inhibitor of normal human T-cell proliferation induced by antigenic or IL-2 stimulation. BCX-34 in normal human T-cells has a deoxyguanosine-independent mechanism to suppress in vitro proliferation. BCX-34 appears to have little effect on T-cell viability. The data suggest that BCX-34 may be useful in the treatment of T-cell proliferative disorders.