Mitozantrone-induced toxicity and DNA strand breaks in leukaemic cells

By applying the fluorometric analysis of DNA unwinding (FADU) the in vitro effect of mitozantrone on DNA strand breaks was studied in seven different human leukaemic/lymphoma cell lines and in fresh leukaemic samples from seven patients with acute myeloid leukaemia refractory to conventional treatment. Pulse exposure to mitozantrone for 30 min invariably caused strand breaks. In the cell lines JM 1, KM3 and RPM I 8420 DNA strand breakage was progressive upon further incubation in drug free medium. These cell lines were killed by pulse exposure to mitozantrone. In the cell lines Molt 4, Daudi, Raji and HL-60, the DNA strand breaks induced by mitozantone were only moderate and these cell lines were also resistant to killing by mitozantrone in vitro. The leukaemic cells of one of the seven patients behaved also like the cell lines that were sensitive and a complete remission was achieved in this patient using mitozantrone as single agent therapy. The other patients with a pattern similar to the resistant cell lines proved to be clinically refractory. Thus mitozantrone induces rapidly progressive DNA strand breaks as early as 30 min in leukaemic cells that are sensitive. The measurement of DNA strand breaks by the fluorometric analysis of DNA unwinding is a rapid method which might predict response to drugs whose major effect is on the induction of strand breaks.