Protection of Bone Marrow Stromal Cells from the Toxic Effects of Cyclo-phosphamide in Vivo and of ASTA-Z 7557 and Etoposide in Vitro by Ammonium TYichloro(dioxyethylene-0-0')tellurate (AS101)

The immunomodulator AS 101 has previously been shown to protect mice from lethal and sublethal doses of cyclophosphamide (CYP). AS101 was also shown to protect BM granulocyte-macrophage colony-forming cells from the toxic effects of ASTA-Z 7557. In the present study we examined the abililty of AS101 to protect functional properties of BM stromal cells from the toxic effects of CYPm vivo or ASTA-Z in vitro. The functional properties of stromal cells from CYP-injected mice were tested with respect to stromal cell number and viability as reflected by the number of colony-forming unit fibroblasts, the ability of established stromal layers to secrete colony-stimulating factor and interleukin 6, as well as the capacity to support hemopoietic cells. All of these parameters were tested from day 1 to day 7 after CYP treatment. We demonstrate that all stromal functions are severely damaged following CYP treatment Pre-treatment of mice with 10 μg AS101 24 h before injection of 250 mg/kg CYP resulted in a significant amelioration of stromal cell functions as early as 24 h following CYP treatment In addition we show that prior incubation of BM cells with AS101 protects the development of stromal colony-forming unit fibroblasts from the toxic effects of ASTA-Z, a potent derivative of CYP, and etoposide, a derivative of podophyllotoxin. These results strongly suggest the usefulness of AS101 in counteracting chemotherapy-induced BM microenvironmental suppression and the important role of the compound as an adjunct treatment of cancer when used in combination with CYP. The data also suggest the effectiveness of AS 101 in purging bone marrow when used concomitantly with ASTA-Z or etoposide.