INDUCTION OF ACUTE-PHASE PROTEINS IN MICE AND HUMANS BY TREATMENT WITH AS101, AN IMMUNOMODULATOR WITH RADIOPROTECTIVE PROPERTIES

AS101 (ammonium trichloro(dioxyethylene-0,0')tellurate) is a new synth etic compound previously described by us as having immunomodulating pr operties and minimal toxicity. Phase II clinical trials are currently in progress with AS101 on cancer patients. AS101 has been recently fou nd to have bath radioprotective and chemoprotective effects on hemopoi esis of irradiated mice or mice treated with various chemotherapeutic drugs. The present research was designed to study the in vivo inductio n of liver acute phase proteins secretion in mice or patients treated with AS101. Induction of these proteins, some of which have the capaci ty to scavenge free radicals, may contribute to radioprotection. We pr esent evidence that treatment with the immunomodulator AS101 increases production of a variety of acute phase proteins. We demonstrate a sig nificant elevation of serum amyloid A (SAA) in sera of treated mice, a s well as an increase in SAA, factor B and ceruloplasmin in sera of pa tients treated with AS101. The same AS101 treatment was shown to decre ase the amount of the negative acute phase protein, albumin. In additi on we show that IL-1, IL-6 and TNF-alpha are important mediators of ch anges in SAA concentrations induced by AS101. Abrogation of SAA produc tion in AS101 treated mice by any one of the anti IL-1R, IL-6R or TNF- alpha antibodies indicates that at least in mice, SAA production is no t controlled by a single extracellular signal, but rather it is regula ted, at the least, by all three cytokines in various combinations. A b etter understanding of the mechanism by which AS101 confers radioprote ction will enable us to use it more effectively in the restoration of hemopoiesis in patients following radiation or suffering from overdose or accidental radiation.