DT388-GM-CSF, a novel fusion toxin consisting of a truncated diphtheria toxin fused to human granulocyte-macrophage colony-stimulating factor, prolongs host survival in a SCID mouse model of acute myeloid leukemia

Citation
Pd. Hall et al., DT388-GM-CSF, a novel fusion toxin consisting of a truncated diphtheria toxin fused to human granulocyte-macrophage colony-stimulating factor, prolongs host survival in a SCID mouse model of acute myeloid leukemia, LEUKEMIA, 13(4), 1999, pp. 629-633
Citations number
17
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
LEUKEMIA
ISSN journal
08876924 → ACNP
Volume
13
Issue
4
Year of publication
1999
Pages
629 - 633
Database
ISI
SICI code
0887-6924(199904)13:4<629:DANFTC>2.0.ZU;2-P
Abstract
Despite significant advances in the treatment of acute myeloid leukemia (AM L), the majority of patients will succumb to drug-resistant AML. To overcom e this resistance, we have developed a novel fusion toxin consisting of the catalytic and translocation subunits of diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor (GM-CSF). In vitro, DT388-GM-CSF demonstrated significant activity against numerous AML cell l ines and fresh AML blasts. To determine its in vivo efficacy, we developed an in vivo model of human AML in severe combined immunodeficiency (SCID) mi ce injected intravenously with 1 x 10(7) HL-60 cells (AML-MS cell line). Th e SCID mice developed abdominal masses, infiltration of the liver and bone marrow, and peripheral blasts with a median survival of 42.5 days. We teste d DT388-GM-CSF, ara-C, human GM-CSF, and DAB(389)IL-5, which were injected intraperitoneally on days 2-6 in this model. DT388-GM-CSF significantly imp roved survival of the SCID mice over Ara-C, DAB(389)IL-2, or control (P < 0 .001). DT388-GM-CSF-treated mice who developed leukemia exhibited no differ ence in the number of GM-CSF receptors (P = 0.39), ligand affinity (P = 0.7 7), or sensitivity (P = 0.56) to DT388-GM-CSF as compared to the controls. Frank leukemia in DT388-GM-CSF-treated mice may be due to incomplete penetr ation of drug into tissues rather than cellular resistance. DT388-GM-CSF is an active therapeutic agent in our SCID mouse model of AML with a unique m echanism of action and differing toxicities than current cytotoxic agents.