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Busulfan induces activin A expression in vitro and in vivo: a possible link to venous occlusive disease
Author(s) -
Dressel Dana,
Ritter Christoph A.,
Sperker Bernhard,
Grube Markus,
Maier Thorsten,
Klingebiel Thomas,
Siegmund Werner,
Beck James F.,
Kroemer Heyo K.
Publication year - 2003
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(03)00190-5
Subject(s) - busulfan , medicine , in vivo , activin type 2 receptors , endocrinology , cytokine , biology , chemistry , cancer research , transplantation , tgf beta signaling pathway , transforming growth factor , hematopoietic stem cell transplantation , microbiology and biotechnology
Purpose Hepatic venous occlusive disease is a severe side effect after administration of busulfan before hematopoietic stem cell transplantation. The syndrome is characterized by liver enlargement, fluid retention, jaundice, and weight gain. Endothelial injury has been described as the precipitating factor. The link between busulfan administration and endothelial damage has not been established thus far. Methods Complementary deoxyribonucleic acid expression arrays were used to screen for busulfan responsive genes in ECV304 cells. Specific messenger ribonucleic acid and protein levels were examined by real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively. Serum samples of 15 pediatric patients with leukemia were analyzed for busulfan and cytokine levels. Results We identified a member of the transforming growth factor β superfamily, activin A, to be induced in the human cell line ECV304 after exposure to busulfan in a time‐ and concentration‐dependent manner. Maximum effects were observed at 120 and 168 hours for activin A messenger ribonucleic acid and protein, respectively. Preincubation with the protein kinase C inhibitor bisindolylmaleimide I (10 nmol/L) abolished activin A induction by busulfan ( P < .05). Activin receptors were detected in ECV304. Both tissue factor and cyclooxygenase 2 were significantly induced by busulfan ( P < .05). In a parallel in vivo study a significant increase in serum activin A concentration was found 4.5 hours after the second dose of busulfan. Conclusion The data demonstrate that busulfan induces activin A both in vitro and in vivo. In view of the multiple targets of activin A (inflammation, proliferation, apoptosis, and coagulation), these findings may be of relevance to our understanding of venous occlusive disease. Clinical Pharmacology & Therapeutics (2003) 74 , 264–274; doi: 10.1016/S0009‐9236(03)00190‐5