ABSTRACT
Mitoxantrone achieves its cytotoxicity by arrest ing the cell cycle at the G2-M and S interphase. It has been shown to induce DNA protein cross links and protein-concealed single-and double strand breaks in DNA as well as nonprotein-associated strand breaks J 1-14! Further research has revealed that one molecular target of mitoxantrone is the enzyme DNA topoisomerase II, which is essential for efficient condensationdecondensation of chromatin and for the segrega tion of replicated daughter chromosomes at cell division. Topoisomerase II changes the topology of DNA strands by introducing transient, double strand breaks through which an intact helix can pass. Topoisomerase II engages in a non-covalent protein-DNA complex that equilibrates with a so-called covalent-cleavable complex.^15,16] The cleavable complex formed between DNA and topoisomerase II is stabilized by mitoxantrone, which thereby prevents religation of transient double-stranded DNAJ15,17i In addition, mitox antrone may induce aggregation and compaction of DNA by electrostatic cross-bindingJ18^
Mitoxantrone has also been shown to evoke generation and release of highly reactive oxygen species to induce non-protein-associated DNA strand breaksJ3-19! There is evidence to suggest that metabolic oxidation of mitoxantrone to reactive 1,4-quinone and 5,8-di-iminequinone intermediates may be an important mechanism of activation of this agent and a prerequisite for its covalent binding to DNAJ18’20,21^ This oxidation may take place in vivo through the action of nitrogen dioxide radicals.^20! Once cells are arrested in the G2 phase of the cell cycle, they may enter cell death pathways. As the under
standing of apoptosis (a physiological process to eliminate cells) grew, several investigators set out to study whether induction of apoptosis may be one of the mechanisms of the therapeutic action of mitoxantrone. Mitoxantrone was shown to induce programmed cell death of certain leukaemia cellsJ22,23^ This evidence was corrobo rated by the demonstration that natural resis tance of acute myeloid leukaemia cells is associated with a lack of apoptosis J24^
In alloreactive mixed lymphocyte cultures, the proliferative response of lymphocytes to antigen is curtailed in the presence of mitoxantrone, and this drug also abolishes the generation of cyto toxic T cellsJ6,7] T-helper cell activity was noted to be diminished, whereas T-suppressor cell func tion was enhanced.^25] Furthermore, mitox antrone profoundly inhibits B lymphocyte function and antibody secretion.t26! Finally, as mentioned above, mitoxantrone inhibits macrophage-mediated myelin degradation ex vivoJ13! In an open trial of mitoxantrone in MS, Gonsette^27] followed patients’ lymphocyte subsets for 3 years and noted a predilective immunosuppressive effect of mitoxantrone on CD4+ lymphocytes and a reduction of the number of B lymphocytes and HLA-DR2+ and IL-2R+ cells by approximately 60% on average. This reduction of the number of B cells and the decreased CD4+:CD8+ ratio was maintained for the whole duration of mitoxantrone therapyJ27^ Similar effects have been observed by othersJ28 ^ Taken together, all pathogenetically relevant cell populations involved in the induction and effec tor phase of immune-mediated demyelination
appear to be targets for the action of mitoxantrone (Table 25.1).
