THE SYNERGISM OF BREQUINAR SODIUM AND CYCLOSPORINE USED IN COMBINATION TO PREVENT CARDIAC ALLOGRAFT-REJECTION IN THE RAT

Brequinar sodium (BQR) is a novel immunosuppressive drug that inhibits cell proliferation by virtue of its disruption of the de novo pyrimid ine biosynthesis. The basis of the immunosuppressive activity of BQR i s distinctively different from that of cyclosporine (CsA), and we have recently evaluated in vivo and in vitro the efficacy of the two drugs when used in combination. Subtherapeutic doses of BQR and CsA were te sted for their ability to prolong heterotopic cardiac allograft surviv al in the MHC- and non-MHC-mismatched ACI-->LEW rat strain combination . The graft survival data derived from these experiments were analyzed using the median-effect analysis to establish the immunosuppressive i nteraction of both drugs. The administration of BQR 3 mg/kg three time s weekly or CsA 2.5 mg/kg daily moderately prolonged cardiac allograft survival, with a mean survival of 10+/-0.5 and 16+/-5.3 days, respect ively. The use of the two drugs in combination with the same dose sche dule exerted a synergistic effect on graft survival, prolonging the gr aft function to a mean of 31+/-5.7 days. Sera from animals treated wit h the two drugs displayed, when compared with single treatment groups (BQR 3 mg/kg and CsA 2.5 mg/kg), significantly (P<0.01) increased in v itro inhibition of lymphocyte proliferation following stimulation with PHA. Finally, a clear correlation between the mean survival time and BQR plasma levels of animals treated with BQR alone or in combination with CsA was seen. Those treatment groups with BQR levels below 2 mug/ ml (1.5 and 3.0 mg/kg/3x/week) had a mean graft survival of less than 10 days). In contrast, recipients treated with a combination of low do ses of BQR and CsA displayed higher drug plasma levels (>2 mug/ml) and longer mean graft survival times. These observations suggest that BQR and CsA may be highly effective when used in combination to prevent o rgan allograft rejection for clinical transplantation.