Mechanism of radioprotection conferred by the immunomodulator AS101.
AS101 [ammonium trichloro (dioxyethylene-0-0') tellurate] is a new synthetic compound previously described by us as having immunomodulating properties and minimal toxicity. Clinical trials are currently in progress with AS101 in AIDS and cancer patients. AS101 has recently been found to have radioprotective effects on hemopoiesis in irradiated mice when administered prior to irradiation. Since the early progenitors, spleen colony-forming units (CFU-S), are the critical cells needed for the reconstitution of the hemopoietic system, the mechanisms of action of AS101 were explored in this study by examining the compound's effect on the recovery of CFU-S, its protective effect on endogenous CFU-S and its effect on self-renewal of CFU-S. We also studied the effect of AS101 on the induction of progenitor cells into the radioresistant S-phase of the cell cycle. On days 1 and 5 after irradiation, the number of CFU-S in the bone marrow and spleen of AS101-treated mice was significantly higher than that of PBS-injected mice. Nine days after sublethal doses of irradiation, the number of endogenous spleen colonies was highest in mice given AS101 every 24 hours or every other day for 1 week prior to irradiation. AS101 administered immediately after irradiation, however, also resulted in an increase in the endogenous CFU-S. The higher number of CFU-S found in each 9-day endogenous spleen colony suggests increased self-renewal of CFU-S in AS101-treated mice. Moreover, we found that AS101 induced a higher number of progenitor cells in the S-phase of the cell cycle. These findings suggest that the radioprotection conferred by AS101 results from induction of progenitor cells in DNA synthesis (S-phase) and from the enhanced stimulation of CFU-S, not only toward proliferation but also toward CFU-S self-renewal.
Kalechman
Y
Y
C.A.I.R. Institute, Department of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Gafter
U
U
Barkai
I S
IS
Albeck
M
M
Sredni
B
B
D000818:Animals; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005030:Ethylenes / Q000008:administration & dosage / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D014916:Whole-Body Irradiation
D005030:Ethylenes; D011837:Radiation-Protective Agents; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate