For definition of Groups, see Preamble Evaluation.
VOL.: 50 (1990) (p. 47)
Chem. Abstr. Name: 1,3,5-Triazin-2(1H)-one, 4-amino-1-b-ribofuranosyl
Azacitidine is a cytostatic agent that has been used since the 1970s for the treatment of acute leukaemia.
Azacitidine was tested for carcinogenicity by intraperitoneal injection in four studies in mice and in two studies in rats and by transplacental exposure in one study in mice. In one study in mice, it accelerated the development of leukaemias; in the two long-term studies and in the transplacental study, it increased the incidence of lymphoid neoplasms. In one of the long-term studies, the incidence of lung adenomas was increased in male mice and that of skin tumours in mice of each sex. In the transplacental study in mice, it also increased the incidences of lung and liver tumours. It accelerated the induction of lung tumours in mice. In rats, it increased the incidence of testicular tumours.
Intraperitoneal administration of azacitidine to rats enhanced the development of liver tumours induced by N-nitrosodiethylamine.
No data were available to the Working Group.
During the early stages of gestation, azacitidine induces embryomortality in mice; during the organogenesis period, multiple, gross structural malformations can be induced; and during later stages of gestation, mainly central nervous system defects have been induced in mice.
Azacitidine is readily deaminated to azauridine and further degraded. It is incorporated into DNA and alters gene expression. In humans, it causes leukopenia.
Azacitidine causes hypomethylation of DNA both in vivo and in vitro.
In one study, azacitidine did not induce dominant lethal mutations in mice. Contradictory results have been reported with respect to the induction of chromosomal aberrations and sister chromatid exchange in human cells. In single studies, azacitidine induced gene mutations and DNA strand breaks in human cells. It induced chromosomal aberrations in Chinese hamster cells, sister chromatid exchange in cloned Chinese hamster cells, gene mutations in Chinese hamster and mouse lymphoma cells and transformation in various cell lines. It induced mitotic recombination and mutations in Drosophila. Azacitidine induced chromosomal aberrations in Vicia faba. In Saccharomyces cerevisiae, it induced gene mutations and mitotic recombination but not chromosomal loss. It induced mutations and DNA damage in Salmonella typhimurium and Escherichia coli.
There is sufficient evidence for the carcinogenicity of azacitidine in experimental animals.
No data were available from studies in humans on the carcinogenicity of azacitidine.
In making the overall evaluation, the Working Group also took note of the following information. Azacitidine is active in a broad spectrum of assays for genetic and related effects, including those involving mammalian cells. Furthermore, azacitidine, a pyrimidine analogue, is incorporated into DNA, causing hypomethylation.
Azacitidine is probably carcinogenic to humans (Group 2A).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 26 (1981) (p. 37); Suppl. 7 (1987) (p. 57)
Last updated: 11 November 1997
See Also: Toxicological Abbreviations