Synergistic antiproliferative effect of recombinant interferon-gamma with
recombinant interferon-alpha on chronic myelogenous leukemia hematopoietic
progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM)
C Carlo-Stella, M Cazzola, A Ganser, G Bergamaschi, P Pedrazzoli, D Hoelzer and E Ascari
Department of Internal Medicine, University of Pavia, Italy.
Recombinant interferons, alpha (rIFN-alpha) and gamma (rIFN-gamma), have
been demonstrated to have significant antitumor activity as single agents
in the treatment of chronic myelogenous leukemia (CML). Due to their
possible synergistic efficacy, a combination rIFN therapy in CML has been
proposed. To establish a biologic basis for this, we have studied the
suppressive effects of rIFN-alpha and rIFN-gamma on the in vitro growth of
CML-derived progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, CFU-GM), the optimal
conditions for rIFN synergism, and the possible role of hematopoietic
accessory cells (T-lymphocytes and monocytes- macrophages) in mediating
rIFN-induced growth inhibition. When added to unseparated bone marrow
cells, rIFN-alpha and rIFN-gamma significantly reduced colony formation,
with 50% inhibition occurring at 71 and 186 U/mL for CFU-GEMM, 40 and 152
U/mL for CFU-Mk, 222 and 1,458 U/mL for BFU-E, and 119 and 442 U/mL for
CFU-GM, respectively. A small amount of rIFN-gamma (5 U/mL) acted
synergistically with increasing doses of rIFN- alpha, and the values of 50%
inhibitory concentrations fell outside the lower limit (10 U/mL) used in
our experiments. This synergy was evident even when rIFN-gamma was added 72
hours after the initiation of cultures; however, it was completely lost
when the target cells were depleted of accessory cells. When a low dose of
rIFN-alpha (5 U/mL) was added to rIFN-gamma, the 50% inhibitory
concentration values were decreased up to tenfold. These studies (1)
confirm that CML-derived hematopoietic progenitors are responsive to the
suppressive activity of both rIFN-alpha and rIFN-gamma in vitro, (2)
demonstrate that different mechanisms are responsible for the suppressive
activity of the two rIFNs, and (3) characterize their synergistic
interaction, providing a basis for future clinical trials aimed at
investigating combination rIFN therapy in CML.
Volume 72,
Issue 4,
pp. 1293-1299,
10/01/1988
Copyright © 1988 by The American Society of Hematology
