EFFECTS OF A NOVEL PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITOR, BCX-34,ON ACTIVATION AND PROLIFERATION OF NORMAL HUMAN LYMPHOID-CELLS

The antiproliferative effect of BCX-34 was tested in normal human peri pheral blood mononuclear cells (PBMCs) induced to proliferate with OKT 3, tetanus toroid, the mixed lymphocyte reaction, or IL-2. In the case of OKT3, tetanus toroid, or the MLR the ICS(50)s ranged between 0.7 a nd 4 mu M. With IL-2, the IC50 was 14.6 mu M. In T-cells purified by r esetting the IC50 with IL-2 was 0.62 mu M In CD4 or CD8 cells obtained by magnetic activated cell sorting the IC(50)s with IL-2 were 0.24 an d 0.62 mu M, respectively. BCX-34 inhibition of proliferation in human PBMCs may not depend entirely upon the accumulation of intracellular dGTP because tetanus toroid-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 viab ility. The results of these studies show that BCX-34 is a potent inhib itor of normal human T-cell proliferation induced by antigenic or IL-2 stimulation. BCX-34 in normal human T-cells has a deoxyguanosine-inde pendent mechanism to suppress in vitro proliferation. BCX-34 appears t o have Little effect on T-cell viability. The data suggest that BCX-34 may be useful in the treatment of T-cell proliferative disorders. (C) 1998 Elsevier Science B.V. All rights reserved.