The clinical pharmacology of mitozantrone

Smyth, John F.; Macpherson, Janet S.; Warrington, P. S.; Leonard, Robert; Wolf, Charles

doi:10.1007/bf00306744

Cited by 37 publications

(6 citation statements)

References 3 publications

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“…CHL was used at 40 µM, which was equivalent to plasma levels measured in mouse pharmacokinetic studies [ 33 , 34 ]. MTX was used at 1.12 µM (500 ng/ml), aligning with levels measured in human plasma following in vivo administration [ 35 , 36 ]. Mitomycin C (MMC; 10,000 pg/ml/30 nmol) was used as a positive control in the micronucleus (MN) assay and was dissolved in dimethyl sulphoxide (final concentration 0.01%; Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Genotoxicity of cytokines at chemotherapy-induced ‘storm’ concentrations in a model of the human bone marrow

Asurappulige,

Thomas,

Morse

2023

Mutagenesis

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Donor cell leukaemia (DCL) is a complication of haematopoietic stem cell transplantation where donated cells become malignant within the patient’s bone marrow. As DCL predominates as acute myeloid leukaemia, we hypothesised that the cytokine storm following chemotherapy played a role in promoting and supporting leukaemogenesis. Cytokines have also been implicated in genotoxicity, thus we explored a cell line model of the human BM to secrete myeloid cytokines following drug treatment, and their potential to induce micronuclei. HS-5 human stromal cells were exposed to mitoxantrone (MTX) and chlorambucil (CHL) and for the first time, were profiled for 80 cytokines using an array. Fifty-four cytokines were detected in untreated cells, of which 24 were upregulated, and 10 were downregulated by both drugs. FGF-7 was the lowest cytokine to be detected in both untreated and treated cells. Eleven cytokines not detected at baseline were detected following drug exposure. TNFα, IL6, GM-CSF, G-CSF and TGFβ1 were selected for micronuclei induction. TK6 cells were exposed to these cytokines in isolation and in paired combinations. Only TNFα and TGFβ1 induced micronuclei at healthy concentrations, but all five cytokines induced micronuclei at storm levels, which was further increased when combined in pairs. Of particular concern was that some combinations induced micronuclei at levels above the mitomycin C positive control, however most combinations were less than the sum of micronuclei induced following exposure to each cytokine in isolation. These data infer a possible role for cytokines through chemotherapy-induced cytokine storm, in the instigation and support of leukaemogenesis in the BM, and implicate the need to evaluate individuals for variability in cytokine secretion as a potential risk factor for complications such as DCL.

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Section: Methodsmentioning

confidence: 99%

Genotoxicity of cytokines at chemotherapy-induced ‘storm’ concentrations in a model of the human bone marrow

Asurappulige,

Thomas,

Morse

2023

Mutagenesis

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“…A rat hepatocyte model and human breast cancer cells both produced similar results [128][129][130][131]. Furthermore, phase II metabolism, namely conjugation with glucuronic acid and reduced glutathione (GSH), plays an important part in the MT detoxification process [133,134]. Numerous preclinical studies have been carried out in rats, rabbits and anaesthetized pigs to identify different metabolites.…”

Section: Metabolism and Its Metabolitesmentioning

confidence: 98%

Overview of Mitoxantrone-a Potential Candidate for Treatment of Breast Cancer

et al. 2022

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Anthraquinones are one of the popular classes of aromatic compounds which possess potential anticancer properties by suppressing the nucleic acid formation and proteins essential to the survival of cancerous cells. Mitoxantrone (MT) is an antibiotic and antineoplastic agent belonging to the anthracycline class of compounds which exhibit minimal incident of drug resistance. It is a synthetic anticancer drug, bound to enzyme topoisomerase IIα inhibitor, and intercalates DNA topoisomerase IIα, preventing re-ligations in DNA strands fragmentation and disruption of DNA repair. The expression of this enzyme was used tumor cells marker because of its key function in cell proliferation. The cleavable complex of topoisomerase IIα is hypothesized to damage the DNA and may enhance apoptosis in tumor cell proliferation. The susceptibility of cells to mitoxantrone is associated with cell topoisomerase II α protein and lowered resistance in breast cancer line cell lines to topoisomerase IIα inhibitors. MT is an ABC-transporter in breast cancer, also designated to be associated with “Breast cancer resistance protein” (BCRP) and it is also a cell cycle non-specific anti-cancer drug and P-glycoprotein substrate. Multiple drug resistance is one of the major drawbacks of this drug which can be avoided by reducing the efflux of the drug from cancer cells by formulating drug by using lipophilic carriers. This manuscript discusses about MT's source, chemistry, physicochemical properties, anti-cancer effects of mitoxantrone and possible pathways, Mitoxantrone targeting topoisomerase II inhibitor for cancer therapy and its mechanism, Various Nano formulation development strategy, toxicity profile, and a few patents related information.

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“…[47][48][49][50][51][52] The a phase represents a rapid distribution of mitoxantrone into erythrocytes, leucocytes and platelets, and the P phase is associated with a redistribution of the drug from blood cells into tissues. [47][48][49][50][51][52] The a phase represents a rapid distribution of mitoxantrone into erythrocytes, leucocytes and platelets, and the P phase is associated with a redistribution of the drug from blood cells into tissues.…”

Section: Distribution After Intravenous Administrationmentioning

confidence: 99%

Mitoxantrone

Dunn¹,

Goa²

1996

Drugs & Aging

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Acute nonlymphoblastic leukaemia (ANLL) is a malignant condition strongly associated with advancing age. Of adult acute leukaemias, 80 to 85% are classified as ANLL, with more than half of all patients being aged over 60 years. Although advancing age has been reported to be a poor prognostic factor in ANLL, recent clinical trials have shown good results in patients aged 60 years and over after coadministration of the anthracenedione antineoplastic agent mitoxantrone with cytarabine. In 1 study in particular, which involved patients aged 60 to 81 years, no correlation was found between increasing age and response rate. However results of a major clinical trial showed age greater than 60 years to be associated with poorer outcomes. Mitoxantrone as initial induction treatment is at least as effective as daunorubicin when either drug is given in combination with cytarabine to patients with previously untreated ANLL. Complete response rates in randomised comparative trials were 53 to 67% after mitoxantrone with cytarabine and 37 to 70% after daunorubicin with cytarabine. In a major US study, significantly more patients achieved a complete response after 1 treatment cycle of mitoxantrone and cytarabine than after daunorubicin and cytarabine. Mitoxantrone has also been effective in inducing complete remissions in patients with relapsed or refractory ANLL, mainly in combination with other antineoplastic agents. Overall survival appears similar after treatment with regimens containing either mitoxantrone or daunorubicin in patients with ANLL, although there have been reports of trends towards increased survival rates with mitoxantrone. The incidence of cardiotoxicity appears low in patients with ANLL who have received mitoxantrone. Lower cardiotoxicity of mitoxantrone relative to daunorubicin has not been conclusively demonstrated in patients with ANLL, although trials in patients with breast cancer have shown mitoxantrone to cause fewer cardiac adverse effects than doxorubicin. This is of particular interest in the elderly, as this group of patients is especially susceptible to the effects of anthracycline-induced cardiac toxicity. Thus, mitoxantrone is a suitable first-line agent for the induction of remission in patients with ANLL, with clearly demonstrated efficacy in patients aged 60 years and over.

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The clinical pharmacology of mitozantrone

Cited by 37 publications

References 3 publications

Genotoxicity of cytokines at chemotherapy-induced ‘storm’ concentrations in a model of the human bone marrow

Genotoxicity of cytokines at chemotherapy-induced ‘storm’ concentrations in a model of the human bone marrow

Overview of Mitoxantrone-a Potential Candidate for Treatment of Breast Cancer

Mitoxantrone

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