ENHANCEMENT OF ALLOGRAFT SURVIVAL BY COMBINATION RS-61443 AND DUP-785THERAPY

Current maintenance immunosuppressive therapy consists of cyclosporine in combination with prednisone and azathioprine. Unfortunately these agents are associated with significant side effects resulting in postt ransplant morbidity and mortality. Therefore, the search for new immun osuppressive agents is essential, not only to improve the results afte r organ transplantation but equally important to reduce morbidity. Rec ently two new antiproliferative drugs, RS-61443 (RS) and DUP-785 (DUP) , have become available. RS (mycophenolate mefotil), a semisynthetic d erivative of mycophenolic acid, inhibits purine de novo synthesis by n oncompetitively and reversibly inhibiting inosine monophosphate dehydr ogenase. DUP (brequinar sodium) inhibits pyrimidine synthesis by rever sibly inhibiting dehydroorotate dehydrogenase. We evaluated subtherape utic combination RS and DUP therapy in the rat (ACI-->LEW) heterotopic heart allograft model. Median graft survival with no treatment, RS (2 0 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 combinat ion therapy (RS 20 mg/kg, DUP 6 or 3 mg/kg 3x/week) was 133 days and 1 21 days, respectively. Furthermore, mean survival following cessation of all therapy at 100 days posttransplant was dramatically prolonged t o 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 act ivity, recipients treated with combination therapy demonstrated no sid e effects and gained body weight during the treatment. To determine if low-dose combination therapy was effective in reversing ongoing rejec tion, treatment was delayed until the 5th postoperative day. Four of 5 recipients (80%) receiving RS monotherapy (60 mg/kg/day), 5 of 5 reci pients (100%) receiving DUP monotherapy (12 mg/kg/day), and 4 of 5 gra fts (80%) receiving combination therapy (RS 40 mg/kg/day and DUP 6 mg/ kg/day) survived over 21 days. Our results demonstrate that combinatio n therapy significantly prolonged graft survival, and that the progres sion of advanced rejection was halted immediately. RS and DUP combinat ion may provide a potent immunosuppressive therapy in clinical transpl antation.