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.