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* Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013;
Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210;
Department of Pharmacology, University of Arizona, College of Medicine, Tucson, AZ 85724;
AmpliMed Corporation, Tucson, AZ 85718; and
¶ Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232
The side effects of cancer chemotherapeutic agents such as mitoxantrone (MIT) in multiple sclerosis (MS) patients justify the search for less toxic drugs. Ethonafide is an anthracene-based antineoplastic drug similar to MIT. With reference to MIT, we examined the effect of ethonafide on experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, an animal model of human MS. We demonstrated that ethonafide is effective in preventing development of EAE as well as in ameliorating the severity of EAE when disease is ongoing. In relatively higher dosages, the effects of ethonafide and MIT on EAE were identical, whereas in lower dosages, MIT seemed more effective. Therapeutic effects of ethonafide were associated with the initial reduction in cellular counts of CD3+, CD4+, CD8+, B220+, CD11b+, NK cells, and NKT cells, followed by recovery of these cells from the bone marrow. Interestingly, the recovered autoreactive T cells in ethonafide-treated animals have reduced capacity to expand and produce cytokines in response to myelin Ag stimulation. Furthermore, CD4+CD25+ regulatory T cells were relatively resistant to depletion and/or recovered faster than T effector cells. The ability of regulatory T cells to resist depletion and replenish quickly during cell ablation therapy may provide an opportunity to reprogram the immune system. Moreover, we provided evidences that ethonafide has less cardiac toxicity compared with MIT. The effectiveness and the low cardiotoxicity of ethonafide might make it a promising immunosuppressive agent for clinical use in treating MS patients.
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 AmpliMed Corporation. F.-D. Shi’s Laboratory is supported by grants from the National Multiple Sclerosis Society, Muscular Dystrophy Association, and Barrow Neurological Foundation.
2 Address correspondence and reprint requests to Dr. Fu-Dong Shi, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013. E-mail address: Fu-Dong.Shi{at}chw.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; MIT, mitoxantrone; EAE, experimental autoimmune encephalomyelitis; Foxp3, Forkhead box p3; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; p.i., postinjection; Treg, regulatory T.
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  A Bar-Or, J Oger, E Gibbs, M Niino, T Aziz, C Renoux, S Alatab, F. Shi, D Campagnolo, F Jalili, et al. Serial combination therapy: is immune modulation in multiple sclerosis enhanced by initial immune suppression? Multiple Sclerosis, August 1, 2009; 15(8): 959 - 964. [Abstract] [PDF]
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