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Blood, 1 July 2002, Vol. 100, No. 1, pp. 334-340
TRANSPLANTATION
Fludarabine induces apoptosis, activation, and allogenicity in
human endothelial and epithelial cells: protective effect of
defibrotide
Günther Eissner,
Gabriele Multhoff,
Armin Gerbitz,
Silvia Kirchner,
Sonja Bauer,
Silvia Haffner,
Daniela Sondermann,
Reinhard Andreesen, and
Ernst Holler
From the Department of Hematology and Oncology,
University of Regensburg, Germany.
Fludarabine is a nonmyeloablative immunosuppressant increasingly
used as a component of alternative conditioning regimens before
allogeneic bone marrow transplantation. It is expected to reduce
conditioning-related toxicity and proinflammatory activation of the
host tissues. However, in our in vitro study, we provide evidence that
2-fluoroadenine 9- -D-arabinofuranoside (F-Ara) as the
active metabolized form of fludarabine damages human microvascular endothelial cells (HMECs) and dermal and alveolar epithelial cell lines
after 48 hours of culture when it is used in pharmacologically relevant
concentrations (range, 10 µg/mL-1 µg/mL). In addition, flow
cytometric analyses revealed a significant up-regulation of
intercellular adhesion molecule 1 and major histocompatibility complex
(MHC) class I molecules by F-Ara, suggesting a proinflammatory activation of HMECs. Cytotoxicity assays demonstrated that target HMECs
pretreated with F-Ara (10 µg/mL) showed increased lysis by allogeneic
MHC class I-restricted cytotoxic T lymphocytes from healthy human
donors. We conclude that, beside its immunosuppressive activities,
F-Ara can be harmful for target tissues of transplantation-related complications and can even stimulate allogeneic immune responses. We
identified the pharmaceutical compound defibrotide as protective against F-Ara- induced apoptosis and alloactivation, importantly, without affecting the antileukemic effect of F-Ara. This observation argues for a potential clinical usage of defibrotide in
pretransplantation conditioning.
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