Biochemical and cytokinetic modulation of L1210 and HL-60 cells by hydroxyurea and effect on 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity.
The modulating effect of hydroxyurea (HU) on 1-beta-D-arabinofuranosylcytosine (ara-C) metabolism and cytotoxicity was evaluated in L1210 cells and the human promyelocytic leukemic cells HL-60. A dose- and time-dependent HU exposure was observed which resulted in maximum deoxycytidine 5'-triphosphate reduction, intracellular ara-C accumulation, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate formation, and cytotoxicity as determined by soft agar cloning. For the L1210 cells, a 5-hr pretreatment of 5 mM HU was optimum. The best result obtained with the HL-60 cells was after a 24-hr exposure of 1 mM HU. There was also a maximum incorporation of ara-C into DNA in both cells following these optimal pretreatment conditions. Cytofluorometric analysis demonstrated that this HU treatment resulted in a maximum accumulation of L1210 and HL-60 cells in the pre-S phase of the cell cycle and that after removal of the HU there was a rapid progression of the cell population through S phase. Because cytotoxicity of ara-C is considered to be predominantly from the inhibition of DNA polymerase and/or the incorporation into DNA, the cytokinetic and biochemical modulatory effects of HU must both be contributing factors to consider in achieving maximal cell kill from this drug sequence.
D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism*; D003570:Cytidine Triphosphate / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000378:metabolism*; D051379:Mice; D012313:RNA / Q000378:metabolism
D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D012313:RNA; D003570:Cytidine Triphosphate; D004247:DNA; D006918:Hydroxyurea