Mechanism of the cytostatic activity of 3-deazaaristeromycin, an inhibitor of adenosylhomocysteine hydrolase.

3-Deazaaristeromycin (100 microM) is cytostatic for the RAW264 mouse macrophage cell line. In cells incubated with 3-deazaaristeromycin, Cell replication is effectively stimulated by 0.5 microM homocysteine thiolactone and no further stimulation occurs at concentrations of homocysteine thiolactone greater than 50 microM. Cell replication occurs when homocysteine thiolactone is administered either simultaneously with, or 4 days after, the administration of 3-deazaaristeromycin. In the presence of 3-deazaaristeromycin, cell replication also occurs when either folate (10 to 100 microM) or hypoxanthine and thymidine are included in the medium. Incorporation of [14C]formate into trichloroacetic acid-precipitable material is inhibited when cells are incubated with 3-deazaaristeromycin, and this inhibition is partially reversed by inclusion of either homocysteine thiolactone or folate in the medium. Experiments showed that adenosylhomocysteine hydrolase is inhibited to the same extent after the cells have been incubated for 4 days with either 3-deazaaristeromycin or 3-deazaaristeromycin and homocysteine thiolactone. The findings suggest that in cells incubated with 3-deazaaristeromycin, the formation of homocysteine from S-adenosylhomocysteine is insufficient for the regeneration of tetrahydrofolate for the synthesis of purines and pyrimidines.