Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion
protein (pIXY 321) enhances high-dose Ara-C-induced programmed cell death
or apoptosis in human myeloid leukemia cells
K Bhalla, C Tang, AM Ibrado, S Grant, E Tourkina, C Holladay, M Hughes, ME Mahoney and Y Huang
Division of Hematology/Oncology, Medical University of South Carolina,
Charleston 29425.
High dose Ara-C (HIDAC) induces programmed cell death (PCD) or apoptosis in
vitro in human myeloid leukemia cells, which correlates with the inhibition
of their clonogenic survival. Hematopoietic growth factors (HGFs)
granulocyte-macrophage colony-stimulating factor (GM- CSF) and
interleukin-3 (IL-3) have been demonstrated to enhance the metabolism and
cytotoxic effects of HIDAC against leukemic progenitor cells. We examined
the effect of pIXY 321 (a GM-CSF/IL-3 fusion protein) on HIDAC-induced PCD
and related gene expressions as well as HIDAC-mediated colony growth
inhibition of human myeloid leukemia cells. Unlike the previously described
effects of HGFs on normal bone marrow progenitor cells, exposure to pIXY
321 alone for up to 24 hours did not suppress PCD in HL-60 or KG-1 cells.
However, exposure to pIXY 321 for 20 hours followed by a combined treatment
with Ara-C plus pIXY 321 for 4 or 24 hours versus treatment with Ara-C
alone significantly enhanced the oligonucleosomal DNA fragmentation
characteristic of PCD. This was temporally associated with a marked
induction of c-jun expression and a significant decrease in BCL-2. In
addition, the treatment with pIXY 321 plus HIDAC versus HIDAC alone
produced a significantly greater inhibition of HL-60 colony growth. These
findings highlight an additional mechanism of HIDAC-induced leukemic cell
death that is augmented by cotreatment with pIXY 321 and may contribute
toward an improved antileukemic activity of HIDAC.
Volume 80,
Issue 11,
pp. 2883-2890,
12/01/1992
Copyright © 1992 by The American Society of Hematology
