Takahiro Yamauchi1, Kanako Uzui2, Rie Nishi2, Hiroko Shigemi2, Takanori Ueda2. 1. Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan tyamauch@u-fukui.ac.jp. 2. Department of Hematology and Oncology, University of Fukui, Eiheiji, Fukui, Japan.
Abstract
BACKGROUND/AIM: 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. MATERIALS AND 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. CONCLUSION: GO and olaparib exerted synergistic cytotoxicity in CD33-positive myeloid leukemia cells in vitro. Copyright
BACKGROUND/AIM: 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. MATERIALS AND METHODS: The humanmyeloid 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. CONCLUSION:GO and olaparib exerted synergistic cytotoxicity in CD33-positive myeloid leukemia cells in vitro. Copyright
Authors: Marloes IJff; Bregje van Oorschot; Arlene L Oei; Przemek M Krawczyk; Hans M Rodermond; Lukas J A Stalpers; H Petra Kok; Johannes Crezee; Nicolaas A P Franken Journal: Int J Mol Sci Date: 2018-08-16 Impact factor: 5.923