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International Agency for Research on Cancer (IARC) - Summaries & Evaluations

MITOXANTRONE
(Group 2B)

For definition of Groups, see Preamble Evaluation.

VOL.: 76 (2000) (p. 289)

Mitoxantrone
CAS No.
: 65271-80-9
Chem. Abstr. Name: 1,4-Dihydroxy-5,8-bis[{2-[(2-hydroxyethyl)amino]ethyl}amino]-9,10-anthracenedione

Mitoxantrone dihydrochloride
CAS No.
: 70476-82-3
Chem. Abstr. Name: 1,4-Dihydroxy-5,8-bis[{2-[(2-hydroxyethyl)amino]ethyl}amino]- 9,10-anthracenedione, dihydrochloride

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Mitoxantrone is a synthetic DNA topoisomerase II inhibitor of the anthracenedione class that has been used in cancer treatment since the mid-1980s. It is used mainly in the treatment of advanced breast cancer, non-Hodgkin lymphoma and certain leukaemias. Recently, it has been used in the treatment of multiple sclerosis.

5.2 Human carcinogenicity data

In the one available, small cohort study of women with early-stage premenopausal breast cancer who had been treated with mitoxantrone in the absence of known or suspected leukaemogenic agents, a substantially increased risk for acute myeloid leukaemia was observed.

Case reports of acute myeloid leukaemia developing in patients treated with mitoxantrone are compatible with the association found in the cohort study.

5.3 Animal carcinogenicity data

No data were available to the Working Group.

5.4 Other relevant data

In humans, mitoxantrone is eliminated biphasically or triphasically, with a terminal half-time of 1972 h. The drug is rapidly taken up by blood cells and is extensively distributed in body tissues. The pharmacokinetics of mitoxantrone is linear up to 80 mg/m2 (standard dose, 12 mg/m2). The elimination half-life was prolonged in patients with impaired hepatic function and in patients with ascites or oedema. Urinary recovery of mitoxantrone as the parent drug or radiolabel is low (< 10%), and significant amounts are still present in body tissues weeks or months after dosing. Few data are available on the metabolism of mitoxantrone in humans, but two inactive metabolites have been reported.

A long elimination phase and tissue retention are also seen in animal species. Active naphthoquinoxaline mitoxantrone metabolites have been reported in some experimental systems.

The main dose-limiting toxic effect of mitoxantrone is myelosuppression, manifest mostly as leukopenia. Other toxic effects include nausea and vomiting, diarrhoea, stomatitis, mucositis and alopecia. Cardiotoxicity is reported in about 3% of patients and is more common with cumulative doses of 160 mg/m2 in previously untreated patients and 120 mg/m2 in previously treated patients, particularly in those who have received anthracyclines.

Mitoxantrone can mutate cells through one of three mechanisms. It intercalates into DNA and causes frameshift mutations in bacteria through that mechanism. Although the drug per se does not interact covalently with the DNA, it is readily oxidized to a species which does form DNA adducts; however, there is currently little evidence that DNA adduct formation is critical for mutagenic events in mammalian cells. The drug is orders of magnitude more toxic in mammalian than in microbial cells. Most of the effects in mammals arise because mitoxantrone is an effective poison of DNA topoisomerase II enzymes. The predominant effects seen to date involve the deletion and/or interchange of large DNA segments. Additionally, mitoxantrone induces polyploidy.

Chromosomal translocations characteristic of those that occur after administration of DNA topoisomerase II inhibitors have been observed in leukaemic cells of patients treated with mitoxantrone-containing regimens. The mode of action of this compound is similar to that of others for which evidence of a leukaemogenic effect is more compelling.

5.5 Evaluation

There is limited evidence in humans for the carcinogenicity of mitoxantrone.

There is inadequate evidence in experimental animals for the carcinogenicity of mitoxantrone.

Overall evaluation

Mitoxantrone is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation.

Synonyms

Mitoxantrone
Mitoxantrone dihydrochloride

 


Last updated: 9 June 2000


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       Toxicological Abbreviations