title: Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells.
abstract: OBJECTIVE
  Gemtuzumab ozogamicin (GO) consists of the cluster of differentiation 33 (CD33) antibody linked to calicheamicin. The binding of GO to the CD33 antigen on leukemic cells results in internalization and subsequent release of calicheamicin, thereby inducing DNA strand breaks. We hypothesized that the poly (ADP-ribose) polymerase inhibitor olaparib might inhibit DNA repair initiated by GO-induced DNA strand breaks, thereby increasing cytotoxicity.
  
  
  METHODS
  The human myeloid leukemia cell line HL-60 and a GO-resistant variant (HL/GO20) were used.
  
  
  RESULTS
  The 50% growth-inhibitory concentrations (IC50) were 24 ng/ml for HL-60 cells and 550 ng/ml for GO-resistant variant HL/GO20 cells. HL/GO20 cells were also refractory to GO-induced apoptosis. CD33 positivity was reduced in HL/GO20 cells. Olaparib-alone did not inhibit the cell growth and did not induce apoptosis in either HL-60 cells or HL/GO20 cells at concentrations of up to 10 μM. When cells were treated with different concentrations of GO in the presence of 10 μM olaparib, the IC50 of GO for HL-60 cells was 13 ng/ml. The combination index was 0.86, indicating synergistic cytotoxicity of GO and olaparib in combination. Such a combination was ineffective for HL/GO20 cells.
  
  
  CONCLUSIONS
  GO and olaparib exerted synergistic cytotoxicity in CD33-positive myeloid leukemia cells in vitro.
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan tyamauch@u-fukui.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Uzui
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nishi
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shigemi
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000079982:Gemtuzumab; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D063268:Sialic Acid Binding Ig-like Lectin 3; D000079982:Gemtuzumab; C531550:olaparib
keywords: DNA repair; Gemtuzumab ozogamicin; HL-60 cells; acute myeloid leukemia; olaparib