Synergistic antiproliferative effect of recombinant interferon-γ with recombinant interferon-α 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, E. Ascari

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Abstract

Recombinant interferons, α (rIFN-α) and γ (rIFN-γ), 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-α and rIFN-γ on the in vitro growth or 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-α and rIFN-γ 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-γ (5 U/mL) acted synergistically with increasing doses of rIFN-α, 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-γ 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-α (5 U/mL) was added to rIFN-γ, 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-α and rIFN-γ 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.

Original languageEnglish
Pages (from-to)1293-1299
Number of pages7
JournalBlood
Volume72
Issue number4
Publication statusPublished - 1988

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Myeloid Progenitor Cells
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hematopoietic Stem Cells
Interferons
Accessories
Inhibitory Concentration 50
T-cells
Macrophages
Growth
Bone Marrow Cells

ASJC Scopus subject areas

  • Hematology

Cite this

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title = "Synergistic antiproliferative effect of recombinant interferon-γ with recombinant interferon-α on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM)",
abstract = "Recombinant interferons, α (rIFN-α) and γ (rIFN-γ), 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-α and rIFN-γ on the in vitro growth or 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-α and rIFN-γ 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-γ (5 U/mL) acted synergistically with increasing doses of rIFN-α, 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-γ 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-α (5 U/mL) was added to rIFN-γ, 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-α and rIFN-γ 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.",
author = "C. Carlo-Stella and M. Cazzola and A. Ganser and G. Bergamaschi and P. Pedrazzoli and D. Hoelzer and E. Ascari",
year = "1988",
language = "English",
volume = "72",
pages = "1293--1299",
journal = "Blood",
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T1 - Synergistic antiproliferative effect of recombinant interferon-γ with recombinant interferon-α on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM)

AU - Carlo-Stella, C.

AU - Cazzola, M.

AU - Ganser, A.

AU - Bergamaschi, G.

AU - Pedrazzoli, P.

AU - Hoelzer, D.

AU - Ascari, E.

PY - 1988

Y1 - 1988

N2 - Recombinant interferons, α (rIFN-α) and γ (rIFN-γ), 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-α and rIFN-γ on the in vitro growth or 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-α and rIFN-γ 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-γ (5 U/mL) acted synergistically with increasing doses of rIFN-α, 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-γ 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-α (5 U/mL) was added to rIFN-γ, 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-α and rIFN-γ 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.

AB - Recombinant interferons, α (rIFN-α) and γ (rIFN-γ), 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-α and rIFN-γ on the in vitro growth or 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-α and rIFN-γ 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-γ (5 U/mL) acted synergistically with increasing doses of rIFN-α, 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-γ 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-α (5 U/mL) was added to rIFN-γ, 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-α and rIFN-γ 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.

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