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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-07-2311.
Submitted July 31, 2002
Accepted January 26, 2003
Differential response of human acute myeloid leukemia cells to Gemtuzumab Ozogamicin (Mylotarg®) in vitro. Role of Chk1 and Chk2 phosphorylation and Caspase 3
Donatella Amico, Anna M Barbui, Eugenio Erba, Alessandro Rambaldi, Martino Introna, and Josee Golay*
Laboratory of Molecular Immunohematology, Department of Immunology and Cell Biology, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy
Department of Oncology, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy
Division of Hematology, Ospedali Riuniti, Bergamo, Italy
Institute of Clinical Medicine, Hematology and Immunology, University of Ancona, Ancona, Italy
* Corresponding author; email: golay{at}marionegri.it.
Gemtuzumab ozogamicin (GO, Mylotarg®) is a humanised anti-CD33 antibody conjugated to the anti-cancer agent calicheamicin, approved for the treatment of CD33+ relapsed acute myeloid leukaemia. We have investigated the effects of GO on four human myeloid leukaemia lines of different FAB types (KG1, THP-1, HL-60 and NB4), observing three different types of response. Exposure to GO (10-1000 ng/ml) induced G2 arrest (up to 80% of the cells) followed by apoptosis (45% of the cells) in HL60 and NB4 cells. By contrast, in THP-1 cells we observed a strong G2 arrest (up to 75% of the cells) with little apoptosis. Finally, the KG1 line was completely resistant to the same concentrations of GO. These different responses did not correlate with the levels of expression of either CD33 or multiple drug resistance proteins, although the highest CsA-inhibitable efflux activity of KG1 cells may play a role in the resistance of this line to the drug. We could show that chk1 and chk2 phosphorylation, but not p53 or p21 expression, correlated with G2 arrest, implicating the ATM/ATR-chk1/chk2 pathway in the cell cycle response to GO. On the other hand apoptosis was associated with caspase 3 activation. Freshly isolated AML cells showed patterns of response to GO in vitro similar to those observed with the cell lines, including phosphorylation of chk2 and caspase 3 activation. Our results suggest that the different molecular pathways induced by the drug in vitro may reflect, at least in part, the variable response to GO obtained in vivo.
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