Inhibition of the pyrimidine biosynthetic pathway with S-8660, an analogue of brequinar sodium, prolongs cardiac allograft survival in rats.
The compound S-8660 is a member of a family of antiproliferative drugs that act on de novo pyrimidine synthesis through selective inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase. S-8660 is highly effective in preventing the development of delayed-type hypersensitivity in mice and in suppressing human mixed-lymphocyte responses. We have tested its ability to prevent cardiac allograft rejection in the ACI (RT1a) to Lewis (RT1(1)) rat strain combination, based on the immunosuppressive activity of this compound and its similarity to another member of this group, brequinar sodium. Daily oral administration of the drug (5 to 20 mg/kg) was begun 2 days before transplantation and extended for periods of time up to 30 days after graft placement. Control grafts were promptly rejected (median survival time, 7.0 +/- 0.5 days). Administration of S-8660 was effective in extending graft survival in a dose-dependent fashion. The efficacy of S-8660 could be improved with a high initial concentration of the drug, followed by a reduction ("tapering") in the level of drug administration (median survival time, 32.0 +/- 4.6 days) or by use in combination with cyclosporine. The differences in the mode of action of S-8660, when compared to cyclosporine or FK 506, suggest that the disruption of de novo pyrimidine synthesis may be an effective and safe addition to a polytherapeutic approach for the prevention of allograft rejection in clinical transplantation.
Cramer
D V
DV
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif.
Chapman
F A
FA
Jaffee
B
B
Jones
E A
EA
Makowka
L
L
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D004139:Dinitrofluorobenzene / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation; D006968:Hypersensitivity, Delayed; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
D001713:Biphenyl Compounds; D011743:Pyrimidines; D011804:Quinolines; D016572:Cyclosporine; C079986:S 8660; D004139:Dinitrofluorobenzene; C030986:pyrimidine