Role of endogenous cytokines secretion in radioprotection conferred by the immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate.
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.
Kalechman
Y
Y
CAIR Institute, Marilyn Finkler Cancer Research Center, Bar Ilan University, Ramat Gan, Israel.
Zuloff
A
A
Albeck
M
M
Strassmann
G
G
Sredni
B
B
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D016207:Cytokines / Q000502:physiology*; D005030:Ethylenes / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D000276:Adjuvants, Immunologic; D016207:Cytokines; D005030:Ethylenes; D011837:Radiation-Protective Agents; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate