MYCOPHENOLATE MOFETIL, AZATHIOPRINE AND CYCLOPHOSPHAMIDE ENHANCED EFFICACY COMBINED WITH CYCLOSPORINE IN RAT CARDIAC TRANSPLANTATION

Anti-proliferative drugs have been used for immunosuppression since th e introduction of clinical transplantation. Most transplant centres in clude azathioprine (Aza) and cyclosporine (CyA) in their standard regi mens, despite several controlled studies having failed to confirm the benefit of this combination. Aza is still. the most commonly used anti -proliferative drug, although no major differences in immunosuppressiv e or toxic effects have been shown between Aza and cyclophosphamide (C ph). Cph as an adjunct to CyA has never been tested in a randomized st udy. Recently, mycophenolate mofetil (MMF) has been developed as the m ost selective inhibitor of T- and B-cell proliferation and promoted as an adjunct to CyA treatment, In the present study, the additive or sy nergistic effects of these three anti-proliferative agents in combined treatment with CyA have been investigated using a rat cardiac transpl antation model in which the immunomodulator linomide (Lin) was include d as a potentiator of rejection. As single drug treatment, CyA, Cph an d MMF, but not Aza, exerted a beneficial effect on graft survival. Thi s prolongation of graft survival was abrogated when any one drug was a dministered together with Lin. The addition of MMF, Aza or Cph to CyA plus Lin treatment improved the graft survival significantly, thus dem onstrating each of the anti-proliferative drugs to exert additive or s ynergistic effects in conjunction with cyclosporine. MMF seemed to be the most effective and least toxic of the drugs tested.