THE EFFECTS OF INHIBITORS OF DNA BIOSYNTHESIS ON THE CYTO-TOXICITY OF 6-THIOGUANINE

  • 1 January 1981
    • journal article
    • research article
    • Vol. 5  (3) , 189-194
Abstract
The effects of several metabolic inhibitors of DNA synthesis on the antiproliferative activity of 6-thioguanine (6-TG) were examined using cultured [mouse] L1210 leukemia cells. The presence of hydroxyurea (HU), 1-.beta.-D-arabinofuranosylcytosine (araC) or 5-fluorodeoxyuridine (FUdR) in cultures of L1210 leukemic cells during exposure to 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. G2 phase cells were also sensitive to 6-TG indicating that at least 2 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 previously unreported lesions may be involved in the cytotoxicity caused by this agent.