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Suppression of chronic myelogenous leukemia colony growth by interleukin-1
(IL-1) receptor antagonist and soluble IL-1 receptors: a novel application
for inhibitors of IL-1 activity
Z Estrov, R Kurzrock, M Wetzler, H Kantarjian, M Blake, D Harris, JU Gutterman and M Talpaz
Department of Clinical Immunology and Biological Therapy, University of
Texas M.D. Anderson Cancer Center, Houston 77030.
In this study, we investigated the role of interleukin-1 beta (IL-1 beta)
in the malignant evolution of chronic myelogenous leukemia (CML) and the
functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral
blood (PB) low-density cells from 38 CML patients were studied in the
colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte
colony culture assay. Samples from patients with early stage,
interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in
the presence of fetal calf serum (FCS), erythropoietin (Epo), and one of
the following: granulocyte-macrophage colony- stimulating factor (10
ng/mL), IL-3 (15 ng/mL), both, or phytohemagglutinin-conditioned medium.
The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a
dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp
contrast, addition of the above growth factors did not augment the colony
growth-promoting effect of FCS and Epo in samples from IFN-resistant
patients; further, adherent cell fractionation or T-lymphocyte depletion
attenuated the "autonomous" colony growth. Lysates of 2.5 x 10(7)
low-density cells from each of six IFN-resistant and six IFN-sensitive CML
patients and three normal volunteers were tested for intrinsic IL-1 beta
content in an enzyme-linked immunosorbent assay and yielded a mean of 610
pg, 54.6 pg, and 49.4 pg of IL-1 beta, respectively (P less than .045).
Interestingly, both soluble IL-1 receptors (sIL-1R) and IL-1 receptor
antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to
500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion,
with maximal inhibition of 64% and 65%, respectively. A similar effect was
noted with the use of anti-IL-1 beta neutralizing antibodies. These data
implicate IL-1 beta in CML disease progression and suggest that the
inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably
be the basis of a novel therapeutic strategy against this disorder.
Volume 78,
Issue 6,
pp. 1476-1484,
09/15/1991
Copyright © 1991 by The American Society of Hematology
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