ABSTRACT
Mitoxantrone (1,4-dihydroxy-5,8-bis[{2-[(2-hydroxyethyl) amino]-ethyl} amino]-9,10-anthracenedionehydrochloride; mitox), 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 and liver and ovarian carcinomas1-5. Soon after its introduction as a cytotoxic agent in cancer chemotherapy, it was found to be immunosuppressive. Wang et al. showed that in vitro alloreactivity was almost completely abrogated by mitox. The drug interfered only with lymphocytes capable of proliferating in response to newly presented antigens without affecting precursor populations. The effects were remarkably long-lasting6,7. This prompted the evaluation of mitox in experimental transplantation, where it was found to prolong greatly the survival of heterotopic cardiac transplants8. This evidence stimulated other investigators to examine whether mitox could modulate the course of experimental autoimmune encephalomyelitis (EAE). In these studies, mitox suppressed both actively and passively induced EAE in mice and guinea-pigs9-12. At the same time, the contribution of macrophages in effecting myelin damage in EAE
was established. Watson et al. demonstrated a blocking effect of mitox on in vitro myelin breakdown by macrophages retrieved from mice with EAE13. Mitox was first tested as a potential diseasemodifying therapy in multiple sclerosis (MS) in 199014. A benefit on clinical and magnetic resonance imaging (MRI) parameters was initially shown in single-arm, unblinded trials14-17. Subsequently, on the basis of two controlled efficacy studies18,19
and an open safety study20, the US Food and Drug Administration approved mitox for worsening relapsing-remitting (RR), secondary progressive (SP) and progressive relapsing (PR) MS in October 2000.
