Molecular and biochemical pharmacology of mitoxantrone.

Evidence has been presented which indicates that Nv: intercalates DNA and additionally causes inter- and intra-strand crosslinking possibly associated with its charged side arms; there is an apparent preference for G-C base pairs; induces single strand and double strand breaks in DNA; strongly inhibits DNA and RNA synthesis; causes nuclear aberrations and chromosomal scattering; induces a block in the G2 phase of the cell cycle with an increase in cellular RNA and polyploidy; is not cell cycle phase-specific with respect to cell kill; does not induce free-radical formation; does not induce lipid peroxidation or superoxide formation; rather it may inhibit ADR-stimulated lipid peroxidation and microsomal superoxide production; does not appear to have a strong potential for cardiotoxicity on the basis of currently postulated mechanisms of action; is capable of inducing cellular resistance in vitro; resistance is associated with an apparent alteration in the cell membrane impairing drug transport into the cell. Although the precise mechanism(s) of tumor cell killing has not been fully defined it is most likely associated with an interaction by Nv with chromosomes resulting in DNA damage, which if not efficiently repaired, will lead to inhibition of nucleic acid synthesis and eventual cell death.