Enhancement of allograft survival by combination RS-61443 and DUP-785 therapy.

Current maintenance immunosuppressive therapy consists of cyclosporine in combination with prednisone and azathioprine. Unfortunately these agents are associated with significant side effects resulting in post-transplant morbidity and mortality. Therefore, the search for new immunosuppressive agents is essential, not only to improve the results after organ transplantation but equally important to reduce morbidity. Recently two new antiproliferative drugs, RS-61443 (RS) and DUP-785 (DUP), have become available. RS (mycophenolate mefotil), a semisynthetic derivative of mycophenolic acid, inhibits purine de novo synthesis by noncompetitively and reversibly inhibiting inosine monophosphate dehydrogenase. DUP (brequinar sodium) inhibits pyrimidine synthesis by reversibly inhibiting dehydroorotate dehydrogenase. We evaluated subtherapeutic combination RS and DUP therapy in the rat (ACI-->LEW) heterotopic heart allograft model. Median graft survival with no treatment, RS (20 mg/kg/day), DUP 3 mg/kg (3x /week), or DUP 6 mg/kg (3x/week) was 6.5, 11.5, 9.5 and 14.5, respectively. Median graft survival with combination therapy (RS 20 mg/kg, DUP 6 or 3 mg/kg 3x/week) was 133 days and 121 days, respectively. Furthermore, mean survival following cessation of all therapy at 100 days posttransplant was dramatically prolonged to 65.7 +/- 43.8 days in animals receiving combination therapy (RS 20 mg/kg/day, DUP 6 mg/kg 3x/week). Despite the potent immunosuppressive activity, recipients treated with combination therapy demonstrated no side effects and gained body weight during the treatment. To determine if low-dose combination therapy was effective in reversing ongoing rejection, treatment was delayed until the 5th postoperative day. Four of 5 recipients (80%) receiving RS monotherapy (60 mg/kg/day), 5 of 5 recipients (100%) receiving DUP monotherapy (12 mg/kg/day), and 4 of 5 grafts (80%) receiving combination therapy (RS 40 mg/kg/day and DUP 6 mg/kg/day) survived over 21 days. Our results demonstrated that combination therapy significantly prolonged graft survival, and that the progression of advanced rejection was halted immediately. RS and DUP combination may provide a potent immunosuppressive therapy in clinical transplantation.