PROTECTION OF BONE-MARROW STROMAL CELLS FROM THE TOXIC EFFECTS OF CYCLOPHOSPHAMIDE INVIVO AND OF ASTA-Z 7557 AND ETOPOSIDE INVITRO BY AMMONIUM TRICHLORO(DIOXYETHYLENE-O-O')TELLURATE (AS101)

The immunomodulator AS101 has previously been shown to protect mice fr om lethal and sublethal doses of cyclophosphamide (CYP). AS101 was als o shown to protect BM granulocyte-macrophage colony-forming cells from the toxic effects of ASTA-Z 7557. In the present study we examined th e abililty of AS101 to protect functional properties of BM stromal cel ls from the toxic effects of CYP in vivo or ASTA-Z in vitro. The funct ional properties of stromal cells from CYP-injected mice were tested w ith respect to stromal cell number and viability as reflected by the n umber of colony-forming unit fibroblasts, the ability of established s tromal layers to secrete colony-stimulating factor and interleukin 6, as well as the capacity to support hemopoietic cells. All of these par ameters were tested from day 1 to day 7 after CYP treatment. We demons trate that all stromal functions are severely damaged following CYP tr eatment. Pretreatment of mice with 10 mug AS101 24 h before injection of 250 mg/kg CYP resulted in a significant amelioration of stromal cel l functions as early as 24 h following CYP treatment. In addition we s how that prior incubation of BM cells with AS101 protects the developm ent 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 AS1 01 in counteracting chemotherapy-induced BM microenvironmental suppres sion and the important role of the compound as an adjunct treatment of cancer when used in combination with CYP. The data also suggest the e ffectiveness of AS101 in purging bone marrow when used concomitantly w ith ASTA-Z or etoposide.