Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats.

Abstract

The introduction of cyclosporine into the immunosuppressive armamentarium has revolutionized transplant surgery with significant improvements in graft survival. The apparent lack of effect of cyclosporine on humoral rejection mechanisms makes the search for other immunosuppressive agents desirable. Two anti-metabolites affecting nucleotide synthesis via different pathways have recently been evaluated for their immunosuppressive potential. DUP-785 (DUP), also known as brequinar sodium, reversibly inhibits de novo pyrimidine synthesis by blocking dihydro-orotate dehydrogenase, thus resulting in the deletion of critical precursors for RNA and DNA synthesis. RS-61443, a morpholinoethyl ester of mycophenolic acid, reversibly and non-competitively blocks inosin monophosphate dehydrogenase, the key enzyme in purine de novo synthesis. A possible additive effect of both drugs was investigated in the rat heart allograft model.