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Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs

Murase, N and Starzl, TE and Demetris, AJ and Valdivia, L and Tanabe, M and Cramer, D and Makowka, L (1993) Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs. Transplantation, 55 (4). 701 - 708. ISSN 0041-1337

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Abstract

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival-far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Murase, N
Starzl, TEtes11@pitt.eduTES11
Demetris, AJ
Valdivia, L
Tanabe, M
Cramer, D
Makowka, L
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 5 May 1993
Date Type: Publication
Journal or Publication Title: Transplantation
Volume: 55
Number: 4
Page Range: 701 - 708
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0041-1337
Other ID: uls-drl:31735062112317, Starzl CV No. 1440
Date Deposited: 08 Apr 2010 17:24
Last Modified: 13 Oct 2017 21:57
URI: http://d-scholarship.pitt.edu/id/eprint/4826

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