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Role of endogenous cytokines secretion in radioprotection conferred by the
immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate
Y Kalechman, A Zuloff, M Albeck, G Strassmann and B Sredni
CAIR Institute, Marilyn Finkler Cancer Research Center, Bar Ilan
University, Ramat Gan, Israel.
The immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate (AS101)
has previously been found by us to have radioprotective properties when
injected into mice before sublethal and lethal doses of irradiation. AS101
also was found to protect mice from hematopoietic damage caused by various
chemotherapeutic drugs. Based on these findings, phase II clinical trials
with cancer patients treated with AS101, in combination with chemotherapy,
are currently underway. In the present study, we wanted to assess the role
of several cytokines in the radioprotection conferred by AS101. We show
that the administration of neutralizing antibodies against interleukin-1
(IL-1) receptor, IL-6 receptor, IL-6, tumor necrosis factor (TNF), or stem
cell factor (SCF) completely abrogates the ability of AS101 to increase the
survival of lethally irradiated mice. Moreover, the injection of each of
these antibodies reduces the ability of AS101 to increase the number of BM,
spleen cells, and the number of circulating neutrophils, lymphocytes, and
platelets in irradiated mice. In addition, these antibodies abrogate the
enhancing effect of AS101 on the secretion of IL-3, IL-6, and
granulocyte-macrophage colony-stimulating factor, all of which decrease
significantly in sublethally irradiated mice. By contrast, the injection of
anti-IL-2 receptor antibody or control Igs to AS101- treated mice does not
interfere with the radioprotective effects of the compound. These results
suggest a role for IL-1, IL-6, TNF alpha, and SCF in the radioprotective
effect of AS101. Because cytokine toxicity remains a significant concern,
the clinical application of AS101, which has no toxicity, is particularly
valuable.
Volume 85,
Issue 6,
pp. 1555-1561,
03/15/1995
Copyright © 1995 by The American Society of Hematology
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