title: Effects of thymidine and hydroxyurea on the metabolism and cytotoxicity of 1-B-D arabinofuranosylcytosine in highly resistant human leukemia cells.
abstract: We have examined the effect of the ribonucleotide reductase inhibitors thymidine (dThd) and hydroxyurea (HU) on the metabolism and cytotoxicity of high concentrations (10 to 100 mumol/L) of cytosine arabinoside (Ara-C) in a deoxycytidine kinase-deficient, highly Ara-C-resistant human promyelocytic leukemic cell subline (HL-60/Ara-C). Administration of dThd or HU (0.5 to 3 mmol/L) in conjunction with high concentrations of Ara-C either sequentially or simultaneously lead to enhanced (and in some cases a supra-additive) inhibition of HL-60/Ara-C suspension culture growth and soft agar colony formation. In addition, exposure of cells to 0.5 mmol/L dThd or HU for 48 hours significantly increased the percentage of HL-60/Ara-C in S-phase. In contrast to previous studies involving low-dose Ara-C administration, we were unable to detect dThd- or HU-mediated increments in Ara-CTP formation in HL-60/Ara-C cells treated with high-dose Ara-C despite reductions in intracellular dCTP pools as great as 65%. However, dThd or HU did increase Ara-C incorporation into newly synthesized DNA. These studies show that administration of dThd or HU in conjunction with high concentrations of Ara-C results in an enhanced antiproliferative effect of Ara-C against Ara-C-resistant leukemic cells deficient in deoxycytidine kinase.
authors.affiliation: Division of Hematology/Oncology, Medical University of South Carolina, Charleston 29425.
authors.forename: K
authors.initials: K
authors.lastname: Bhalla
authors.forename: P
authors.initials: P
authors.lastname: Swerdlow
authors.forename: S
authors.initials: S
authors.lastname: Grant
mesh_terms: D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage*; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D013936:Thymidine / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
chemical_list: D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D004247:DNA; D013936:Thymidine; D006918:Hydroxyurea