Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide.
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.
Eissner
Günther
G
Department of Hematology and Oncology, University of Regensburg, Germany. guenther.eissner@klinik.uni-regensburg.de
Multhoff
Gabriele
G
Gerbitz
Armin
A
Kirchner
Silvia
S
Bauer
Sonja
S
Haffner
Silvia
S
Sondermann
Daniela
D
Andreesen
Reinhard
R
Holler
Ernst
E
D017209:Apoptosis / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D011089:Polydeoxyribonucleotides / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology*
D011089:Polydeoxyribonucleotides; D020011:Protective Agents; D018799:Intercellular Adhesion Molecule-1; C036901:defibrotide; D014740:Vidarabine; C024352:fludarabine