SUPPRESSION OF GRAFT-VERSUS-HOST DISEASE BY SUCCINYL ACETONE IN A RAT ALLOGENEIC BONE-MARROW TRANSPLANTATION MODEL

The efficacy of succinyl acetone (SA, 4,6-dioxoheptanoic acid) was explored in the allogeneic rat bone marrow transplant model of graft-vs.-host disease. Lethally irradiated Wistar Furth rats receiving Fischer 344 allogeneic bone marrow and spleen cells developed severe GVHD, resulting in mortality at 25-45 days posttransplant. Treatment for 14 days with 250 mg/kg/day of SA by Alzet osmotic pumps implanted subcutaneously 3 days before cell transfer prevented GVHD and produced long-term survivors that were allogeneic hematopoietic chimeras. SA doses below 250 mg/kg/day and treatment for less than 14 days were less efficacious. Initiation of SA therapy could be effectively delayed up to 7 days after BMT. Pharmacokinetic studies with i.v. bolus administration in normal CD rats revealed a plasma mean residence time that increased with dose and a systemic clearance that decreased with dose. Three dose-dependent half lives were apparent (ca. 7-18 min, 0.8-3 hr, and 12 hr). The s.c. bioavailability was ca. 82%. Relatively constant plasma SA levels were obtained with s.c. Alzet osmotic pumps, indicating no change in clearance with continuous exposure. Allogeneic BMT exerted no major influence upon SA clearance. These studies show that SA is a robust therapeutic agent that suppressed GVHD in the allogeneic rat BMT model under a variety of circumstances.