VOL.: 76 (2000) (p. 317)
CAS No.:
Chem. Abstr. Name: N-[4-(9-Acridinylamino)-3-methoxyphenyl]methane-sulfonamide
Amsacrine is a synthetic DNA topoisomerase II inhibitor used primarily in the treatment of leukaemia in adults and children.
5.2 Human carcinogenicity data
No data were available to the Working Group.
5.3 Animal carcinogenicity data
Amsacrine was tested by intraperitoneal administration in one assay for lung adenomas in mice; no increase in incidence was reported. In a single study in rats given amsacrine by intravenous administration, small-intestinal adenomas and adenocarcinomas were induced in a dose-dependent fashion in males and females, and a few adenocarcinomas of the large intestine were seen in males and females at the high dose. The incidences of squamous-cell papillomas and carcinomas of the skin were increased in males and females, those of keratoacanthomas and of fibromas of the skin were increased in males, and those of mammary fibroadenomas and adenocarcinomas were increased in females. All of these increases were dose-dependent.
The occurrence of intestinal carcinomas in rats of each sex and the occurrence of skin tumours after intravenous administration of a chemical are unusual.
5.4 Other relevant dataIn humans, amsacrine is eliminated biphasically, with an elimination half-time of 5–9 h. The drug is rapidly taken up by nucleated blood cells, with an overall cell:plasma ratio over 24 h of 8:1, and is distributed to other tissues. Preliminary studies suggest that the oral bioavailability of amsacrine is poor, and there is currently no oral formulation of the drug. About 35% of an intravenous dose was excreted renally over 72 h, with 12% as unchanged amsacrine; biliary recovery in two patients was up to 36%. Biphasic elimination was also observed in a number of animal species. In mice and rats, > 50% of a radiolabelled dose was excreted in the bile within 2 h, and 74% of the dose was recovered in the faeces of mice by 72 h. The results of studies in humans and animals demonstrate the importance of renal and hepatic function in amsacrine clearance. In animals, much of a radiolabelled dose of amsacrine was excreted as metabolites, some of which were cytotoxic. There are currently no data on the metabolism of amsacrine in humans.
In human and animal species, the main toxic effect of amsacrine is myelosuppression, especially leukopenia. Other common toxic effects are nausea and vomiting, mucositis, alopecia and diarrhoea. Less common effects include hepatotoxicity and cardiotoxicity. Amsacrine does not bind covalently to DNA. It appears to mutate cells through two mechanisms. In mammals, amsacrine is an effective poison of DNA topoisomerase II enzymes, leading to cellular accumulation of protein-masked double-stranded DNA breaks and, with time, a variety of chromosomal aberrations. It is also an effective recombinogen, its predominant effects appearing to involve the deletion and/or interchange of large DNA segments. Amsacrine also induces both polyploidy and aneuploidy. It is a frameshift mutagen in bacteria and bacteriophages, and this property may be related to its intercalating action. Potent protein-masked DNA breakage and clastogenic effects occur in human cells in vitro and in animal cells in vivo.5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of amsacrine. There is sufficient evidence in experimental animals for the carcinogenicity of amsacrine. Overall evaluationAmsacrine is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Synonyms
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Toxicological Abbreviations