Protective and Restorative Role of ASI01 in Combination with Chemotherapy

The immunomodulator AS101 has been found previously by us tostimulate the secretion of high levels of interleukin 1 and colony stimulating factor (CSF) in vitro, as well as the production of CSF in vivo inmice models. These cytokines are known to induce proliferation anddifferentiation of hematopoietic progenitor cells from the spleen and bonemarrow (BM) and to protect mice from DNA-damaging agents. Thepresent studies were designed to evaluate the effects of prolonged treatment with AS101 on myelopoiesis, BIVIcellulari!), and CSF secretion inmice treated with a sublethal dose of cyclophosphamide (CYP) and onthe survival of mice undergoing treatment with lethal doses of thiscompound. In this model, the hematopoietic progenitors were suppressedduring the overbound phase of myelopoiesis resulting from the cytotoxiceffects of CYP. This allowed the detection of a significant proliferarneeffect of AS101 in vivo on BM colony-forming units granulocyte-macrophageprogenitor cells, BM cellularity, and the secretion of CSF. Moreover, AS101 protected these animals from the lethal effects of high dosesof CYP. These protective effects were demonstrable only when AS101was administered to mice prior to CYP treatment. The only exceptionwas CSF secretion by spleen cells that had been reconstituted whenAS101 was administered both prior to and following CYP treatment.AS101 was found to have a synergistic effect with CYP in the treatmentof tumor-bearing mice, suggesting that the combination of these twomodalities provides a more effective treatment of their tumors. Theseresults strongly suggest an immunoregulatory role for AS101 in counteracting the chemotherapy-induced hematopoietic suppression as well asusefulness as adjunct treatment of cancer when used in combination withCYP.