COMBINED IMMUNOSUPPRESSIVE THERAPY WITH LOW-DOSE FK506 AND ANTIMETABOLITES IN RAT ALLOGENEIC HEART-TRANSPLANTATION

Following rat heterotopic heart allotransplantation, low to lethal dos es of the antimetabolites mizoribine (MIZ), R9-61443 (RS), and AZA wer e given alone or in combination with subtherapeutic doses of FK506 (0. 04 mg/kg/day) for 14 days after transplantation. With the median effec t analysis of Chou and Kahan for quantitative drug interactions, subst antial therapeutic synergism was demonstrated between FK506 and nontox ic doses of MIZ (2.5, 5, and 10 mg/kg/day) or AZA (5, 30, and 45 mg/kg /day), which was particularly evident with the lowest dose MIZ (2.5 mg /kg/day). When FK506 was used in combination with MIZ or AZA but not w ith RS, the maximum effect (peak median graft survival) was enhanced s ignificantly from 15 days (MIZ alone) to 26 days (P<0.05), and from 19 days (AZA alone) to 32 days (P<0.01). In contrast, RS interacted with FK506 no more than additively. Although RS was the most powerful sing le antimetabolite, the best overall survival was obtained by combining AZA and FK506. The addition of FK506 did not significantly increase t he percent mortality and LD(50) of the antimetabolites.