Immunologic, toxicologic and marrow transplantation studies in dogs given dimethyl myleran

Hematologic, pathologic and immunosuppressive effects of single doses of dimethylbusulfan (DMB) were evaluated in 39 dogs with and without infusion of previously stored autologous marrow. Three to 5 mg DMB/kg caused depression of blood cell counts for over 40 days, but ultimately 6 of 7 dogs recovered completely. 7.5 mg DMB/kg produced fatal marrow aplasia within 17 days of administration of the drug in 10 dogs not given marrow while 8 of 11 dogs given autologous marrow 8 to 36 hr after DMB administration survived with complete hemopoietic recovery. All 7 dogs given 10 mg DMB/kg followed by autologous marrow infusion survived. Only 1 of 4 dogs given 15 mg DMB/kg and autologous marrow infusion survived. Three died with severe gastrointestinal toxicity and infection. DMB showed only a weak immunosuppressive effect at the doses studied as determined by antibody titers against sheep red blood cells and bacteriophage phiX174 and by the development of lymphocytotoxic antibodies after transfusion of allogeneic blood products. Transplantation of allogeneic marrow failed in 4 dogs given 10 mg DMB/kg indicating lack of suppression of cellular immunity by DMB. Successful and sustained marrow engraftment was achieved in only 2 of 8 additional dogs given 10 mg DMB/kg preceded by administration of rabbit antidog antithymocyte serum (ATS) over a period of 6 days. A dose of 7.5 mg DMB/kg is lethal in the dog. Stored autologous marrow is effective in restoring hemopoietic function and securing survival of dogs following otherwise lethal and even supralethal doses of DMB. Even at a supralethal dose DMB showed only weak suppression of humoral and cellular immunity. Allogeneic marrow grafts after DMB were only occasionally possible after a combination of DMB and the immunosuppressive agent ATS.