Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat.
BACKGROUND
This study investigated the effect of the antineoplastic agent gemcitabine (dFdC) in combination with cyclosporine (CsA) or with FK506 on acute heart allograft rejection in a rat model.


METHODS
Transplantations were performed in the fully allogeneic Lewis-to-Brown Norway strain combination. dFdC, CsA, and FK506 single-drug therapy and combinations of dFdC with CsA and FK506 were administered at various dosages starting on day 1 to prevent and on day 4 to treat acute rejection until day 20. Animals who did not reject their graft were intraperitoneally injected with 108 splenic donor-type lymphocytes. In addition, Lewis and third-party skin grafts were transplanted to these animals.


RESULTS
Mean graft survival times under CsA, FK506, and dFdC monotherapy were 18.3/63.7 days (1 mg/5 mg per kg), 41.7 days, and 24.7/38.7 days (100 microg/150 microg per kg), respectively. CsA and FK506 in combination with dFdC prolonged graft survival to more than 100 days (CsA) and more than 95.2 days (FK506). Graft survival after treatment of an ongoing rejection was 21.5/38.3 days for CsA (1 mg/5 mg per kg) and 17.7/59.2 days for dFdC (100 microg/150 microg per kg). The combination of CsA+dFdC prompted indefinite survival of five of six hearts. Lymphocyte inoculation did not induce graft rejection. Notably, none of the Lewis, but all third-party, skin grafts were rejected immediately. Histomorphologic analysis of grafted hearts, however, demonstrated typical features of chronic rejection.


CONCLUSIONS
The combination of CsA and FK506 with low-dose dFdC exerts a synergistic effect in the prevention and treatment of acute allograft rejection in this model. Although chronic rejection could not be prevented, strain-specific tolerance was achieved. Therefore, combining standard immunosuppressants with dFdC is a novel, promising strategy for prevention and treatment of acute allograft rejection.
Jeske
Hans-Christian
HC
Department of Transplant Surgery, D. Swarovski Research Laboratory, Innsbruck University Hospital, Innsbruck, Austria.
Oberladstätter
Jürgen
J
Schneeberger
Stefan
S
Hittmair
Anton
A
Klima
Günther
G
Obrist
Peter
P
Ollinger
Robert
R
Roberts
Kurt
K
Schubert
Heinrich
H
Steurer
Wolfgang
W
Margreiter
Raimund
R
D000208:Acute Disease; D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004357:Drug Synergism; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007519:Isoantigens / Q000494:pharmacology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology*; D014019:Tissue Donors; D023001:Transplantation Tolerance / Q000187:drug effects*; D000093542:Gemcitabine
D007166:Immunosuppressive Agents; D007519:Isoantigens; D003841:Deoxycytidine; D016572:Cyclosporine; D016559:Tacrolimus; D000093542:Gemcitabine