Mechanism of synergistic cell killing by hydroxyurea and cytosine arabinoside.
Synergistic cell killing of human lymphoblastic leukemia cell line, CCRF-CEM, occurred when hydroxyurea (HU) was administered before 1-beta-D-arabinofuranosylcytosine (ara-C). At the optimal dose of HU (1mM), the ara-CTP concentration increased 4-fold and the intracellular accumulation of ara-C increased 4-fold, while the dCTP concentration decreased by more than 50%. Increased intracellular accumulation of ara-C after HU treatment was also observed in human acute myelogenous leukemic cells in circulating blood. Therefore, the synergistic cell kill of HU and ara-C may be the consequence of greater inhibition of DNA polymerase by the increased level of ara-CTP in the presence of the decreased concentration of the natural substrate of this enzyme, dCTP. This synergism was not due to an increased incorporation of ara-C into DNA since the treatment of cells with HU did not enhance the ara-C incorporation into DNA but rather suppressed it.
D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity*; D007945:Leukemia, Lymphoid; D019384:Nucleic Acid Synthesis Inhibitors
D004273:DNA, Neoplasm; D003845:Deoxycytosine Nucleotides; D003854:Deoxyribonucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D003561:Cytarabine; D006918:Hydroxyurea