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The effects of several metabolic inhibitors of DNA synthesis on the antiproliferative activity of 6-thioguanine (6-TG) were examined using cultured L1210 leukemia cels. The presence of hydroxyurea (HU), 1-beta-D-arabinofuranosylcytosine (araC), or 5-fluorodeoxyuridine (FUdR) in cultures of L1210 leukemic cells during exposure of 6-TG did not increase the degree of inhibition of cellular replication produced by the 6-thiopurine, but instead partially protected cells against the delayed cytotoxicity of 6-TG, implying that DNA replication was essential for the expression of cytotoxicity by the purine antimetabolite. Consistent with these results was the finding that synchronized L1210 cells exposed to 6-TG were the most susceptible to the cytotoxic action of the 6-thiopurine during G1/S and S phase. However, G2 phase cells were also sensitive to 6-TG indicating that at least two metabolic lesions are responsible for the production of cytotoxicity. Alkaline sucrose gradient sedimentation of L1210 cells exposed to 6-TG revealed that the purine analog causes structural changes in DNA suggesting that these hitherto unreported lesions may be involved in the cytotoxicity caused by this agent.