Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis

ArticleinJournal of Neuroimmunology 151(1-2):55-65 · July 2004with8 Reads
DOI: 10.1016/j.jneuroim.2004.02.008 · Source: PubMed
Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).
    • "As autoimmune diseases are mediated by the activation and expansion of autoreactive lymphocytes, one possible therapeutic strategy to treat autoimmunity is to target the proliferating autoreactive cells with antimitotic drugs. Previous work has shown that inhibiting the proliferation of disease-causing T cells with topoisomerase II inhibitors is effective at reducing disease in animals with EAE, a mouse model of MS [4, 5]. Unfortunately, there are adverse side-effects associated with this class of drugs, the most notable being cardiotoxicity. "
    [Show abstract] [Hide abstract] ABSTRACT: The hallmark of autoimmunity is the activation and proliferation of autoreactive lymphocytes. Therefore, one potential strategy to treat autoimmunity is to target the proliferating autoreactive lymphocytes with antimitotic drugs. Paclitaxel and peloruside are two microtubule-stabilizing drugs that halt cell proliferation by stabilizing microtubules in the G(2)/M phase of the cell cycle. C57BL/6 mice treated for 5 consecutive days with paclitaxel or peloruside had a reduced incidence and significantly delayed development of EAE, a mouse model of MS. Although paclitaxel and peloruside were effective at inhibiting T cell proliferation in vitro, paclitaxel was shown to be ineffective at preventing the proliferation of autoreactive T cells in vivo during the 5-day treatment period. However, after the 5-day treatment, the ability of splenocytes or LN cells to proliferate in vitro was reduced significantly, suggesting that drug treatment targeted late but not early proliferative events in the animal. Moreover, in paclitaxel-treated, MOG-immunized mice, there was a complete inhibition of the recruitment of myeloid cells (especially macrophages) to the peripheral lymphoid organs. These results indicate that microtubule-stabilizing drugs are effective at reducing disease but require a prolonged exposure to paclitaxel in vivo to alter proliferation in the myeloid and lymphoid cell compartments.
    Full-text · Article · Sep 2009
  • [Show abstract] [Hide abstract] ABSTRACT: Pixantrone is an anthraquinone-based inhibitor of topoisomerase II. It is similar to both the anthracycline doxorubicin and the anthracenedione mitoxantrone, but lacks the 5,8-dihydroxy substitution pattern of mitoxantrone, and has a tricyclic system unlike the tetracyclic structure seen with anthracyclines. Anthracyclines are the most active drugs in lymphoma therapy, but their use is limited by their cumulative and irreversible cardiotoxicity. Pixantrone was developed to improve the toxicity profile of the current anthracyclines and anthracenediones while maintaining their activity. Interestingly, pixantrone showed no measurable cardiotoxicity compared with its parent compound mitoxantrone or other anthracyclines at equi-effective doses in several animal models. Together with its superior cytotoxic activity in leukaemia and lymphoma models, these features render the drug a promising candidate for clinical development in indolent and aggressive non-Hodgkin's lymphoma. In this review, the latest results of the use of pixantrone in indolen-t and aggressive non-Hodgkin's lymphomas are summarised.
    Article · Sep 2005
  • [Show abstract] [Hide abstract] ABSTRACT: Pixantrone is an immunesuppressor similar to mitoxantrone but with lower cardiotoxicity. We evaluated the effect of pixantrone on B cells and lymphomononuclear cells in the course of acute EAE. Pixantrone reduced the number of B cells and suppressed myelin basic protein (MBP) specific IgG production. In vitro, pixantrone induced apoptosis of rat B lymphocytes in a way similar to mitoxantrone. In addition, pixantrone inhibited antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production, during EAE. These findings suggest a similar mechanism of action for pixantrone and mitoxantrone on the effector function of lymphomonocyte B and T cells.
    Article · Dec 2005
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