Purine Arabinosides as Inhibitors of Human Haemopoietic Progenitor Cells

Four purine arabinosides that inhibit varicella-zoster virus (VZV) replication in vitro were tested as inhibitors of colony formation by progenitor cells from normal human bone marrow. In general, erythroid burst forming cells (BFU-E) were more sensitive to inhibition by these compounds than were either erythroid colony forming cells (CFU-E) or granulocyte/macrophage colony forming cells (CFU-GM). A 50% reduction in colony formation (IC50) was observed for BFU-E in the presence of 8 μM 6-methoxypurine arabinoside. Adenine arabinoside and hypoxanthine arabinoside had IC50 values of 1 μM and 4 μM respectively, whereas 6-ethoxypurine arabinoside was not inhibitory (IC50 > 50 μM). Enzyme studies showed that both 6-methoxypurine arabinoside and adenine arabinoside were converted to hypoxanthine arabinoside by adenosine deaminase. 6-Ethoxypurine arabinoside was a much less efficient substrate. When the BFU-E assays were performed in the presence of an inhibitor of adenosine deaminase, 6-methoxypurine arabinoside became non-inhibitory. In contrast, adenine arabinoside became much more inhibitory (IC50 = 0.03 μM). The potency of hypoxanthine arabinoside was unaffected. Thus, incubation of 6-methoxypurine arabinoside and adenine arabinoside under conditions appropriate for the BFU-E assay resulted in the in situ conversion of these compounds to hypoxanthine arabinoside. Biotransformation of compounds must be considered in the assessment of toxicity in vitro.