Synergistic effect of vincristine with tacrolimus or sirolimus in prevention of acute heart allograft rejection in the rat.
The application of multiple immunosuppressive therapy for organ transplantation could enhance therapeutic efficacy, while minimizing the toxicity of individual drugs used in the regimen. In this study, the effect of the combined therapy of vincristine (VCR) with tacrolimus (FK506) or sirolimus (rapamycin, RAPA) was tested in prevention of acute heart allograft rejection in the rat. A Brown Norway (BN, RT 1(n)) to Lewis (LEW, RT 1(1)) rat combination was used in a heart allografting model. VCR was administered intraperitoneally once daily, while FK506 and RAPA were given by gavage once daily for 14 days after transplantation. There were dose-related prolongations of mean survival time (MST) to monotherapy of VCR, FK506, or RAPA. The MST in combination therapy indicated that a synergistic interaction was produced when compared with the respective monotherapies: VCR 0.05 mg/kg/day + FK506 0.5 mg/kg/day (16.00 +/- 1.79 days, P = 0.001; combination index (CI) = 0.557); VCR 0.05 mg/kg/day + FK506 1.0 mg/kg/day (29.00 +/- 10.54 days, P = 0.001; CI = 0.598); VCR 0.05 mg/kg/day + RAPA 0.2 mg/kg/day (17.33 +/- 1.97 days, P = 0.001; CI = 0.500); and VCR 0.05 mg/kg/day + RAPA 0.4 mg/kg/day (21.17 +/- 3.19 days, P = 0.001; CI = 0.838). Combination therapy of VCR and FK506 or RAPA produced synergistic effects in prevention of acute heart allograft rejection in the rat.
Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada.
Wenlei
W
Jiang
Jingen
J
Jiang
Dasheng
D
Xu
Xiang
X
Wang
Shijie
S
Qi
Jun
J
Ouyang
Anlun
A
Ma
Minh Diem
MD
Vu
Kupa K
KK
Bilolo
Huifang
H
Chen
D000208:Acute Disease; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D014750:Vincristine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D007166:Immunosuppressive Agents; D014750:Vincristine; D020123:Sirolimus; D016559:Tacrolimus