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)

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  • 1 October 1988
    • journal article
    • research article
    • Vol. 72  (4) , 1293-1299
Abstract
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.