Eissner, Günther and Multhoff, Gabriele and Gerbitz, Armin and Kirchner, Silvia and Bauer, Sonja and Haffner, Silvia and Sondermann, Daniela and Andreesen, Reinhard and Holler, Ernst (2002) Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood 100 (1), pp. 334-40.
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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-beta-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 microg/mL-1 microg/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 microg/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.
|Institutions:||Medicine > Abteilung für Hämatologie und Internistische Onkologie|
|Subjects:||600 Technology > 610 Medical sciences Medicine|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||15 Apr 2010 05:16|
|Last Modified:||15 Apr 2010 05:16|