The effects of arabinosyl-6-mercaptopurine (Ara-6-MP) on lymphocyte blastogenic responses in vitro to mitogens were studied. Ara-6-MP was not degraded in the cultures until after 5 days of incubation. Levels of drug of 30 μg/ml or greater significantly inhibited blastogenic responses to phytohemagglutinin, streptolysin O and allogeneic leukocytes as measured by [3H]thymidine incorporation (greater than 50 per cent reduction). Levels over 100-200 μg ml inhibited thymidine incorporation over 90 per cent, but complete inhibition was not achieved at any dose up to 300 μg ml. Morphological examination of parallel replicate cultures revealed that blastogenesis characterized by cell enlargement and the development of cytoplasmic basophilia was not significantly inhibited by the drug. Inhibition, at least at higher drug levels, began within 2 hr after exposure of the cells to the drug. Inhibition was completely reversible if the drug was washed from the cultures after 48 hr of continuous exposure and partially reversible when washed from the cultures after up to 96 hr of continuous exposure. In contrast to thymidine incorporation, uridine and leucine incorporation were only slightly inhibited by Ara-6-MP. These studies suggest that Ara-6-MP is a potent reversible and incomplete specific inhibitor of DNA synthesis among mitogen-stimulated, cultured leukocytes in vitro and that it might be an inhibitor of the proliferative phase of the specific immune response in vitro. In addition, these studies indicate that the morphological events associated with lymphocyte transformation can proceed in the virtual absence of DNA synthesis.
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