TY - JOUR
T1 - Diphtheria toxin fused to human gm-csf is toxic to primary malignant progenitors from patients with AML, JMML and CMML
AU - Frankel, A.
AU - Eaves, C.
AU - Hall, P.
AU - Kreitman, R.
AU - Lilly, M.
AU - Heran, M.
AU - Bc,
PY - 1998
Y1 - 1998
N2 - Human GM-CSF fused to a truncated diphtheria toxin (DT388GM-CSF) was expressed in E. coli, denatured, refolded, and purified by anion exchange and size exclusion chromatography. This fusion toxin was found to be toxic in vitro to GM-CSF receptor-bearing cell lines and primary leukemic clonogenic progenitors from patients with AML (27/28), JMML (5/7), and CMML (12/21), whereas, clonogenic progenitors in normal bone marrow samples (6/6) were insensitive to the protein under identical treatment conditions. Cell lines bearing mutant GM-CSF receptors (alpha term 1 plus beta) and cell lines with overexpression of anti-apoptotic proteins (Bcl-2 and Bcl-xl) were less sensitive to DT388-GM-CSF, and showed an increased IC50 of 2.5- to 25-fold. SCID mice inoculated IV with cells from a human leukemic cell line (HL60) and then treated on days 2 to 6 with 84 ug/kg/d of DT388-GM-CSF i.p. had a significantly (p < 0.001) prolonged survival (median survival = 83 days vs 45 days for the untreated animals) and 6 mice in the test group survived > 150 days. DT388-GM-CSF has thus been shown to display marked antileukemic efficacy in vitro and in vivo and merits further evaluation as a potential therapeutic agent for the treatment of several human leukemias.
AB - Human GM-CSF fused to a truncated diphtheria toxin (DT388GM-CSF) was expressed in E. coli, denatured, refolded, and purified by anion exchange and size exclusion chromatography. This fusion toxin was found to be toxic in vitro to GM-CSF receptor-bearing cell lines and primary leukemic clonogenic progenitors from patients with AML (27/28), JMML (5/7), and CMML (12/21), whereas, clonogenic progenitors in normal bone marrow samples (6/6) were insensitive to the protein under identical treatment conditions. Cell lines bearing mutant GM-CSF receptors (alpha term 1 plus beta) and cell lines with overexpression of anti-apoptotic proteins (Bcl-2 and Bcl-xl) were less sensitive to DT388-GM-CSF, and showed an increased IC50 of 2.5- to 25-fold. SCID mice inoculated IV with cells from a human leukemic cell line (HL60) and then treated on days 2 to 6 with 84 ug/kg/d of DT388-GM-CSF i.p. had a significantly (p < 0.001) prolonged survival (median survival = 83 days vs 45 days for the untreated animals) and 6 mice in the test group survived > 150 days. DT388-GM-CSF has thus been shown to display marked antileukemic efficacy in vitro and in vivo and merits further evaluation as a potential therapeutic agent for the treatment of several human leukemias.
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M3 - Article
AN - SCOPUS:33748594194
SN - 0301-472X
VL - 26
SP - 745
JO - Experimental Hematology
JF - Experimental Hematology
IS - 8
ER -