Anticancer Drugs Acting via Radical Species


Mitoxantrone, an anthraquinone derivative bearing polyamine side chains, can be considered as a partial analog of the anthracyclines, including the hydroxyquinone function but not the amino sugar fragment. This compound was obtained as an analog of ametantrone, which was initially prepared as a component of ballpoint pen ink, but a routine screening by NCI led to recognition of its antitumor activity. The reasoning that led to the design of mitoxantrone68 was based on the observation that a large number of antileukemic agents shared a common N–O–O triangular pharmacophore, which was also present in the anthracyclines and involved the daunosamine amino group (Figure 4.24). The introduction of the two phenolic hydroxy groups in ametantrone allowed to envision two sets of N–O–O triangles and had the advantage of allowing the elimination of the daunosamine amino group, which was considered to have some influence in the cardiotoxicity of the anthracyclines.


Mitoxantrone is active in breast cancer, acute promyelocytic or myelogenous leukemias, and androgen-independent prostate cancer. Although early reports seemed to indicate that its cardiotoxicity was lower than that of the anthracyclines,70 this claim has been subsequently challenged.71 Mitoxantrone has been approved for treatment of secondary progressive multiple sclerosis (MS).72 The rationale for this application stems from the fact that MS is considered to be an autoimmune disease in which a heightened immune action results in the destruction of the myelin of the central nervous system, causing nerve impulses to be slowed or halted and leading to the symptoms of MS. Because chemotherapeutic 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 been fully elucidated. As discussed 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.73 Later, it was found that mitoxantrone can be activated by formaldehyde and is able, like adriamycin, to form adducts that stabilize double-stranded DNA, blocking the progression of RNA polymerase during transcription and producing truncated RNA transcripts.74 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. Although mitoxantrone can be reductively activated to a semiquinone free radical, this process has a low efficiency and the compound undergoes less redox cycling in vitro than the anthracyclines.


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