The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice.
The effects of cyclosporine (CsA), sirolimus (RAPA), and/or brequinar (BQR) were examined in a vascularized heterotopic heart transplant model in mice. Untreated C3H (H-2k) recipients reject C57 BL/10 (H-2b) heart allografts at a mean survival time (MST) of 7.7 +/- 1.4 days. A 7-d intravenous (i.v.) infusion by osmotic pump of CsA at doses of 5.0, 10.0, or 20.0 mg/kg extended heart allograft survival to 9.8 +/- 1.3 d (NS), 15.0 +/- 5.1 d (P < 0.01) or 15.0 +/- 1.9 d (P < 0.01), respectively. RAPA delivered i.v. for 7 d at a dose of 0.1 mg/kg produced an MST of 13.0 +/- 7.5 d; 0.2 mg/kg, 20.0 +/- 10.9 d; and 0.4 mg/kg, 15.8 +/- 4.1 d (all P < 0.01). A 7-d alternate-day (q.o.d.) course of oral gavage with BQR (0.5, 1.0, or 2.0 mg/kg) produced survivals of 12.0 +/- 2.4 d, 17.6 +/- 3.4 d, and 20.0 +/- 4.1 d, respectively (all P < 0.01). The combination of 2.5 mg/kg CsA with 0.05 mg/kg RAPA extended graft survival to 18.2 +/- 2.9 d (P < 0.01), and 5.0 mg/kg CsA with 0.1 mg/kg RAPA prolonged survival to 23.0 +/- 9.0 d (P < 0.01). These combinations represent synergistic interactions based upon combination index (CI) values of 0.1-0.6. Although 7-d courses of 0.5 mg/kg CsA (7.3 +/- 1.0 d; NS), 0.01 mg/kg RAPA (7.6 +/- 0.9 d; NS), or 0.125 mg/kg BQR (7.6 +/- 0.9 d; NS) were individually ineffective, the triple-drug combination prolonged the MST to 64.6 +/- 32.7 d (P < 0.005; CI = 0.001), with 2/5 grafts beating for more than 100 d. Similar results were produced by 14-day therapy in the BALB/c (H-2d) to C3H combination.
Tu
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Department of Surgery, University of Texas Medical School at Houston 77030.
Stepkowski
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SM
Chou
T C
TC
Kahan
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BD
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D011798:Quinaldines
D001713:Biphenyl Compounds; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus; C046943:brequinar; D011798:Quinaldines