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Malignant Progenitors From Patients With Acute Myelogenous
Leukemia Are Sensitive to a Diphtheria
Toxin-Granulocyte-Macrophage Colony-Stimulating Factor Fusion Protein
Donna E. Hogge,
Cheryl L. Willman,
Robert J. Kreitman,
Marc Berger,
Philip D. Hall,
Kenneth J. Kopecky,
Chris McLain,
Edward P. Tagge,
Connie J. Eaves, and
Arthur E. Frankel
From the Terry Fox Laboratory, British Columbia Cancer Agency,
Vancouver, British Columbia, Canada; the Department of Pathology,
University of New Mexico Cancer Center, Albuquerque, NM; the Laboratory
of Molecular Biology, National Cancer Institute, National Institutes of
Health, Bethesda, MD; the Departments of Surgery and Pharmaceutical
Sciences, Medical University of South Carolina, Charleston, SC; the
SWOG Statistical Center, Fred Hutchinson Cancer Research Center,
Seattle, WA; and the Comprehensive Cancer Center at Wake Forest,
Winston Salem, NC.
We have previously demonstrated that human granulocyte-macrophage
colony-stimulating factor (GM-CSF) fused to a truncated diphtheria
toxin (DT388-GMCSF) kills acute myelogenous leukemia (AML) cell lines
bearing the GM-CSF receptor. We now report that exposure of malignant
cells from 50 different patients with AML for 48 hours in culture to
DT388-GMCSF reduces by a median of 1.6 logs (range, 0 to 3.7 logs) the
number of leukemic cells capable of forming colonies in semisolid media
(leukemic colony-forming cells [CFU-L]) with a median
IC50 of 3 × 10 12 mol/L (range, 5 to
>4,000 × 1012 mol/L). Furthermore, the cell kill is
dependent on the presence of high-affinity GM-CSF receptors on leukemic
blasts, because CFU-L from 27 of 28 AML samples expressing  35 GM-CSF
receptors per cell were inhibited by the toxin, whereas the colony
growth from all 4 leukemic samples (2 AML, 1 acute lymphoblastic
leukemia [ALL], and 1 prolymphocytic leukemia [PLL]) that had less
than 35 receptors per cell was unaffected by the drug. Sensitivity of
CFU-L to DT388-GMCSF was seen regardless of the clinical responsiveness of the patient's leukemia to standard chemotherapy agents. In contrast, clonogenic cells from normal bone marrow formed colonies at
near control numbers after exposure to much higher toxin concentrations (4 × 109 mol/L) than those required to kill CFU-L from
most patients. Thus, leukemic progenitors isolated directly from the
peripheral blood of most AML patients show the same sensitivity to
DT388-GMCSF as previously demonstrated for AML cell lines. Under the
same conditions of exposure, normal hematopoietic progenitors are
relatively unaffected by DT388-GMCSF, suggesting its potential as a
therapeutic agent in AML.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 589-595
© 1998 by the American Society of Hematology.
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