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* Neurology IV, Neurological Institute Foundation "Carlo Besta",
Consiglio Nazionale delle Ricerche, Institute of Chemistry of Molecular Recognition, and
Cell Therapeutics, Europe, Milan, Italy; and
Istituto di Ricerche Biomediche "Antoine Marxer"-Merck Serono, Turin, Italy
Pixantrone (BBR2778) (PIX) and mitoxantrone share the same mechanism of action because both drugs act as DNA intercalants and inhibitors of topoisomerase II. PIX is an interesting candidate immunosuppressant for the treatment of autoimmune diseases because of its reduced cardiotoxicity compared with mitoxantrone. The clinical response to conventional immunosuppressive treatments is poor in some patients affected by myasthenia gravis (MG), and new but well-tolerated drugs are needed for treatment-resistant MG. PIX was tested in vitro on rat T cell lines specific for the immunodominant peptide 97–116 derived from rat acetylcholine receptor (AChR), and showed strong antiproliferative activity in the nanomolar range. We demonstrate in this study that PIX administration reduced the severity of experimental autoimmune MG in Lewis rats. Biological and immunological analysis confirmed the effect of PIX, compared with vehicle-treated as well as mitoxantrone-treated experimental autoimmune MG rats. Anti-rat AChR Abs were significantly reduced in PIX-treated rats, and AChR content in muscles were found increased. Torpedo AChR-induced T cell proliferation tests were found reduced in both in vitro and ex vivo experiments. The effectiveness and the reduced cardiotoxicity make PIX a promising immunosuppressant agent suitable for clinical investigation in MG, although additional experiments are needed to confirm its safety profile in prolonged treatments.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grant RF2002.159 from the Italian Ministry of Health.
2 Address correspondence and reprint requests to Dr. Fulvio Baggi, Neurology IV, Neurological Institute Foundation "Carlo Besta", Via Celoria 11, 20133 Milan, Italy. E-mail address: baggi{at}istituto-besta.it
3 Abbreviations used in this paper: PIX, pixantrone; MTX, mitoxantrone; EAE, experimental allergic encephalomyelitis; MG, myasthenia gravis; EAMG, experimental autoimmune MG; AChR, acetylcholine receptor; TAChR, Torpedo AChR; LNC, lymph node cell; 
-BTX, -bungarotoxin.
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