Yz. Tu et al., THE SYNERGISTIC EFFECTS OF CYCLOSPORINE, SIROLIMUS, AND BREQUINAR ON HEART ALLOGRAFT SURVIVAL IN MICE, Transplantation, 59(2), 1995, pp. 177-183
The effects of cyclosporine (CsA), sirolimus (RAPA), and/or brequinar
(BQR) were examined in a vascularized heterotopic heart transplant mod
el in mice. Untreated C3H (H-2(k)) recipients reject C57 BL/10 (H-2(b)
) 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), resp
ectively, 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, 1
5.8 +/- 4.1 d (all P < 0.01). A 7-d alternate-day (q.o.d.) course of o
ral 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 c
ombinations 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-dru
g 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 wer
e produced by 14-day therapy in the BALB/c (H-2(d)) to C3H combination
.