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Mitoxantrone

FIGURE 4.21 Similarities between anthracyclines, ametantrone and mitoxantrone.

agents diminish the numbers of white blood cells, it should slow down or halt this autoimmune destruction.

The mechanism of action of mitoxantrone has not yet been fully elucidated. As it will be mentioned in Chapter 7, this drug is a classic intercalating agent that acts as a topoisomerase II poison. Mitoxantrone can also be oxidatively activated to bind DNA; although the mechanism and binding properties have not been resolved, peroxidase-mediated free radical formation suggested that a mitoxantrone reactive intermediate may be involved in the observed DNA strand damage.59 More recently, it was found that mitoxantrone can be activated by formaldehyde and is able, like adriamycin, to form adducts which stabilize double-stranded DNA, blocking the progression of RNA polymerase during transcription and producing truncated RNA transcripts.60 This explains why mitoxantrone is particularly active in myeloid tumors, which are known to have increased levels of formaldehyde, formed from spermine and other polyamines by neutrophile-generated ROS.61 Although mitoxantrone can be reductively activated to a semiquinone free radical, this process has a low efficiency and the compound undergoes less redox cyclying in vitro than the anthracyclines.62 The adducts of formaldehyde-activated mitoxantrone occur preferently at CpG and CpA sequences, and their formation is stimulated by cytosine methylation.63 Thus, the reaction of mitoxantrone with formaldehyde leads to the hydroxy-methyl derivative 4.30, which forms a covalent bond with a guanine amino group to give the covalent adduct 4.32, presumably through iminium cation 4.31 as an intermediate. The involvement of a single covalent bond has been proved by mass spectrometry, and further stabilization of the complex by hydrogen bonding has been suggested on the basis of molecular modeling studies (Fig. 4.22).64

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