The cytotoxic effects of gemtuzumab ozogamicin (mylotarg) in combination with conventional antileukemic agents by isobologram analysis in vitro.
BACKGROUND
The CD33 antigen is expressed on leukemia cells in most patients with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), and in 20% of patients with acute lymphoblastic leukemia (ALL), while it is absent from pluripotent hematopoietic stem cells and nonhematopoietic cells. Gemtuzumab ozogamicin (GO) is an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, which is a potent cytotoxic agent that causes double-strand DNA breaks, resulting in cell death. GO was developed against CD33 antigen-positive leukemias. The aim of this study was to investigate the cytotoxic effects of this agent in combination with conventional antileukemic agents.


METHODS
The cytotoxic effects of GO in combination with antileukemic agents were studied against human CD33 antigen-positive leukemia HL-60, U937, TCC-S and NALM20 cells. The leukemia cells were exposed simultaneously to GO and to the other agents for 4 days. Cell growth inhibition was determined using a MTT reduction assay. The isobologram method was used to evaluate the cytotoxic interaction.


RESULTS
GO produced synergistic effects with mitoxantrone, additive effects with cytarabine, daunorubicin, idarubicin, doxorubicin, etoposide and 6-mercaptopurine, and antagonistic effects with methotrexate and vincristine.


CONCLUSIONS
Our findings suggest that the simultaneous administration of GO with most agents studied would be advantageous for antileukemic activity. The simultaneous administration of GO with methotrexate or vincristine would have little cytotoxic effect, and this combination may be inappropriate. These findings may be useful in clinical trials of combination chemotherapy including GO or other monoclonal antibodies linked to calicheamicin.
Tanaka
Masaru
M
Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, 3311-Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
Kano
Yasuhiko
Y
Akutsu
Miyuki
M
Tsunoda
Saburo
S
Izumi
Tohru
T
Yazawa
Yasuo
Y
Miyawaki
Shuich
S
Mano
Hiroyuki
H
Furukawa
Yusuke
Y
D000617:Aminoglycosides / Q000008:administration & dosage / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D000079982:Gemtuzumab; D018922:HL-60 Cells; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D000922:Immunotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy*; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D008942:Mitoxantrone / Q000008:administration & dosage; D063268:Sialic Acid Binding Ig-like Lectin 3; D020298:U937 Cells; D014750:Vincristine / Q000008:administration & dosage
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D000922:Immunotoxins; D063268:Sialic Acid Binding Ig-like Lectin 3; D003561:Cytarabine; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D000079982:Gemtuzumab; D008942:Mitoxantrone; D015122:Mercaptopurine; D008727:Methotrexate; D015255:Idarubicin; D003630:Daunorubicin