Mitoxantrone for the treatment of advanced breast cancer: Single-agent therapy in previously untreated patients

Cornbleet, M. A.; Stuart-Harris, R.; Smith, Ian; Coleman, Robert E.; Rubens, Robert; McDonald, Michael; Mouridsen, Henning T.; Rainer, H.; Oosterom, A.T. van; Smyth, John F.

doi:10.1016/0277-5379(84)90122-6

Cited by 79 publications

(28 citation statements)

References 5 publications

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“…stabilized DNA-topoisomerase II-cleavable complex) contributes to the cytotoxic effect of mitoxantrone (4). However, in addition to this mechanism it has also been demonstrated that the oxidation products of mitoxantrone (catalyzed by horseradish peroxidase) form a covalent complex with DNA in vitro (5), and similar drug-DNA adducts were subsequently also detected when mitoxantrone was oxidized in vitro by the human enzyme myeloperoxidase (6).…”

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A Molecular Understanding of Mitoxantrone-DNA Adduct Formation

Parker

Buley

Evison

et al. 2004

Journal of Biological Chemistry

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When mitoxantrone is activated by formaldehyde it can form adducts with DNA. These occur preferentially at CpG and CpA sequences and are enhanced 2-3-fold at methylated CpG sequences compared with non-methylated sites. We sought to understand the molecular factors involved in enhanced adduct formation at these methylated sites. This required, first, clarification of factors that contributed to the formation of adducts at CpG sites. For this purpose mass spectrometry of an oligonucleotide duplex (containing a single CpG adduct site) was used to confirm the presence of an additional carbon atom (derived from formaldehyde) on the drug-DNA complex. The effect of 3-flanking sequences was revealed by electrophoretic analysis of oligonucleotidedrug adducts, and the preferred adduct-forming site was identified as 5-CGG-3. Radiolabeled studies of drug-DNA adducts confirmed that the site of attachment involved the exocyclic amino of guanine. Molecular modeling analysis of the relative stability of the intercalated form of mitoxantrone was consistent with observed adduct-forming potential of CG sites with varying flanking sequences. The known preference for adduct formation at methylated CG sites was confirmed by energetics calculations and shown to be due to a shift of equilibrium of the intercalated form of the drug from the major groove (at CG sites) to the minor groove (at methylated CG sites). This increases the relative amount of drug that is located adjacent to the N-2 exocyclic amino of guanine in the minor groove, where covalent linkage is facilitated. These results account for the enhanced covalent binding of mitoxantrone to methylated CG sequences and provide a molecular model of the interactions.

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confidence: 99%

A Molecular Understanding of Mitoxantrone-DNA Adduct Formation

Parker

Buley

Evison

et al. 2004

Journal of Biological Chemistry

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“…However, when used in combination with melphalan (Perez et al, 1984) cumulative myelosuppression became a problem. Mitoxantrone (Novantrone [R] Lederle) is an anthracenedione which has equivalent activity to doxorubicin in advanced breast cancer, but with a lower incidence of nausea, vomiting and alopecia and also less cardiac toxicity (Cornbleet et al, 1984;Neidhart et al, 1983;Mouridsen et al, 1983). We have developed a combination regimen 3M, comprising mitoxantrone, mitomycin C and methotrexate.…”

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A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer

Powles

Jones²,

Judson³

et al. 1991

Br J Cancer

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Summary This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m 2 (day 1), mitozantrone 7 -8 mg m-2 (day I and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The Table 1. A total of 217 patients were entered into the study and after exclusions because of protocol violation (prior chemotherapy) there remained 106 patients who received 3M and 105 patients who received VAC. The median age was 55 (range 36-77) years for 3M and 58 (range 30-76) years for VAC. The median disease-free interval (primary diagnosis to first relapse) was similar for 3M (16 months) and VAC (15 months) and the median time from relapse to start of chemotherapy was also similar (8 months) for both regimens. Most patients (66% for both 3M and VAC) had received prior endocrine therapy consistent with our policy of using endocrine treatment for first relapse.

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“…However, the cumulative dose-dependent cardiomyopathy produced by the drug severely restricts its therapeutic usefulness (Minow et al, 1975) and this problem has lead to the development of new structurally related anthraquinone drugs. One of these is mitoxantrone, which is currently used in advanced breast cancer and acute leukaemias (Cornbleet et al, 1984). Although mitoxantrone does not exhibit the same broad spectrum of anti-tumour activity as does adriamycin, the incidence and severity of cardiotoxicity is markedly reduced (Smith, 1983).…”

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The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells

Duthie

Grant²

1989

Br J Cancer

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Summary The cytotoxic properties of quinones, such as menadione, are mediated through one electron reduction to yield semi-quinone radicals which can subsequently enter redox cycles with molecular oxygen leading to the formation of reactive oxygen radicals. In this study the role of reduction and oxidation in the toxicity of mitoxantrone was studied and its toxicity compared with that of adriamycin and menadione. The acute toxicity of mitoxantrone was not mediated through one-electron reduction, since inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells against oxidative damage, did not affect its toxicity. Adriamycin was the most potent inhibitor of protein and RNA synthesis of the three quinones. Menadione, at concentrations up to 25 ftM, did not inhibit either protein or RNA synthesis unless dicoumarol, an inhibitor of DT-diaphorase, was also present. The two-electron reduction of menadione by DT-diaphorase is therefore a protective mechanism in the cell. This enzyme also protected against the toxicity of high concentrations (100 pM) of mitoxantrone. The inhibitory effect of mitoxantrone, but not of menadione or adriamycin, on cell growth was prevented by inhibiting the activity of cytochrome P450-dependent mixed function oxidase (MFO) system using metyrapone. This suggests that mitoxantrone is oxidised to a toxic intermediate by the MFO system.

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Mitoxantrone for the treatment of advanced breast cancer: Single-agent therapy in previously untreated patients

Cited by 79 publications

References 5 publications

A Molecular Understanding of Mitoxantrone-DNA Adduct Formation

A Molecular Understanding of Mitoxantrone-DNA Adduct Formation

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer

The role of reductive and oxidative metabolism in the toxicity of mitoxantrone, adriamycin and menadione in human liver derived Hep G2 hepatoma cells

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