ABSTRACT
Mitoxantrone (1,4-dihydroxy-5,8-bis((2-hydro-xyethyl-amino)-ethyl)-amino) 9,10anthracenedione hydrochloride), molecular weight 517 Da, is a synthetic antineoplastic agent first discovered in 1978. It has proven therapeutic efficacy in advanced breast cancer, non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, chronic myeloid leukemia, liver carcinoma, and ovarian carcinoma.[1-5] Soon after its introduction as a cytotoxic agent in cancer chemotherapy, it was found to be immunosuppressive. Wang and colleagues showed that in vitro alloreactivity was almost completely abrogated by mitoxantrone.[6,7] The drug interfered only with lymphocytes capable of proliferating in response to newly presented antigens without affecting precursor populations. The effects were remarkably long-lasting. This prompted evaluation of mitoxantrone in experimental transplantation, where it was found to prolong greatly the survival of heterotopic cardiac transplants.[8] This evidence stimulated other investigators to examine whether mitoxantrone could modulate the course of experimental autoimmune encephalomyelitis (EAE). In these studies, mitoxantrone suppressed both actively and passively induced EAE in mice and guinea pigs.[9-12] At the same time, the contribution of macrophages in effecting myelin damage in EAE was established. Watson et al. demonstrated a blocking effect of mitoxantrone on in vitro myelin breakdown by macrophages retrieved from mice with EAE.[13]
Mitoxantrone was first tested as a potential disease-modifying therapy in multiple sclerosis (MS) in 1990.[14] Benefit on clinical and magnetic resonance imaging (MRI) parameters was initially shown in single-arm, unblinded trials.[14-17] Subsequently, on the basis of two controlled efficacy studies[18,19] and an open safety study,[20] in October 2000 the US Food and Drug Administration (FDA) approved mitoxantrone for worsening relapsing-remitting MS, secondary progressive MS, and progressing relapsing MS.
