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)

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.