AZACITIDINE

This substance was considered bya previous Working Group, in October 1980, under the title 5-azacytidine (IAC, 1981). Since that time, new data have become

available, and these have been incorporated into the monograph and taken into consideration in the present evaluation.

1. ehemical and Physical Data

1.1 Synonyms

ehem. Abstr. Services Reg. No.: 320-67-2

ehem. Abstr. Name: 1,3,5-Triazin-2(1H-one,4-amino-1--ribofuranosyl

Synonym: Antibiotic U 18496; 5-azacytidine; ladakamycin; NSC 102816;

lJ- 18496; WR- 183027
1.2 Structural and molecular formulae and molecular weight

N "' N

L IL

NH2

'N~O

HOH2C

C8H 12N40S

MoL. wt: 244.2

1.3 Chemical and physical properties of the pure substance

From Winkley and Robins (1970), unless otherwse specified
(a) Description: White crystalline powder

-47-

48

IARC MONOGRAHS VOLUME 50

(b) Me/ting-point: 235-237C (decmposes) (c) Optical rotation: ( 0: J if . + 26.6 C (c = 1.00; in water)
(d) Solubility Soluble in warm water (40 mg/ml), cold water (14 mg/ml), 0.1 N

hydrochloric acid (28 mg/ml) and 0.1 N sodium hydroxide (43 mg/ml);

soluble in 35% ethanol (14.2-15.0 mg/l), acetone (1 mg/ml), chloroform

(1 mg/ml), hexane (1 mg/ml) and dimethyl sulfoxide (52.7 mg/ml) (von Hoff et al., 1975)

(e) Spectrosocopy data: Ultraviolet, infrared and nuclear magnetIc resonance

spectra have been reported (Beisler, 1978).
(j Stability Very unstable in aqueous media, rapid degradation to complex
products occurring within hours of

dissolution in intravenous solutions at

room temperature (Reynolds, 1989)

1.4 Technical products and impurities

Trade name: Mylosar Azacitidine is available as a lyophilized powder in vials containing 100 mg of the compound with 100 mg mannitol for reconstitution as injections of 5 mg/ml (von
Hoff et al., 1975).
2. Production, Occurrence, Use and Analysis
2.1 Production and occurrence
(a) Production

Azacitidine, a pyrimidine analogue of cytidine with a nitrogen substituted for a

5-carbon, can be isolated from a culture of the bacterium Streptoverticillium ladakanus, but has also been prepared by synthetIc methods. One reported method involved treatment of the trimethylsilyl derivative of 4-amino- 1,3,5-triazn-2-one with 2,3,5-tri-O-acetyl-D-ribofuranosyl bromide, followed by deacetylation to give
azacitidine.(Winkley & Robins, 1970).

Azacitidine is synthesized in the Federal Republic of Germany (Chemical

Information Servces, 1989-90).

(b) Occurrence

Azacitidine is produced by the bacterium Streptoverticillium ladakanus (Winkley & Robins, 1970).
2.2 Use

Azacitidine is a cytostatic agent. It has ben used mainly in the treatment of

acute leukaemia, either as intravenous or intramuscular injections or as

AZAcmDINE

49

intravenous infusions at a daIly level of 40-750 mg/m2 (Weiss et al., 1972; Skoda,
1975; von Hoff et aL., 1975, 1976; von Hoff & Slavik, 1977; Wade, 1977; Glover et aL.,

1987; Reynolds, 1989). It is used alone, or in combination with vincristine,

vinblastine, prednisone, cytarabine or amsacrine, at a daily dose of 50- 150 mg/m2

azacitidine. It has also been tested for use in the treatment of a variety of solid
tumours (Glover et al., 1987).
2.3 AnaJysis

Azacitidine can be quantified in blood by microbiological assay (Pittillo & Woolley, 1969) and in plasma by high-p-erformance liquid chromatography with ultraviolet detection (Rustum & Hoffman, 1987).

3. Biological Data Relevant to the Evaluation of

earcinogenic Risk to Humans

3.1 Carcinogenicity studies in animaIs
(a) lntraperitoneal injection

Mouse: ln a screening assay based on the accelerated induction of leukaemia in a strain highly susceptible to development of this neoplasm, 40 AK female mice, two months of age, were given six intraperitoneal injections of azacitidine at 1.5
mg/kg bw (purity unspecified) over 20 days, and, because of toxicity, six injections of
azacitidine at 0.8 mg/kg bw over the following 30 days. Alhtreated mice had died of

leukaemia by 60 days. A control group of 40 females survived free of disease for the
observation time of 120 days (Vesely & Cihk, 1973).

ln a screening assay based on the accelerated induction of lung tumours in a strain highly susceptible to developmentof this neoplasm, three groups of ten male

and ten female NHe mice, six to eight weeks of age, received intraperitoneal injections of azacitidine (purity unspecified), in a vehicle composed of saline,
polysorbate-SO, carboxyethyl cellulose and benzyl alcohol, three times a week for eight weeks (total doses, 33, 62 and 90 mglg bw (which was the maxmum tolerated
dose)). Control groups received 24 intraperitoneal injections of 0.1 ml vehicle or

were untreated. AlI animaIs were killed 24 weeks after the first injection. The
numbers of mice with lung tumours, calculated on the basis of survivors of each sex,
were 6/11 (54%), 5/15 (33%) and 8/19 (42%) in the groups receiving the high, mid

and low doses, respectively. The results for untreated and vehicle-treated groups were expressed only as per cent tumour incidence; thus, 22% (males) and 17% (females) of untreated controls and 26% (males) and 23% (females) of

50

lARe MONOGRAHS VOLUME 50

vehicle-treated controls developed lung tumours. The number of lung tumours per mouse (counted grossly) in animaIs of each sex treated with the highest dose was
0.73 :f 0.22 (SE), which was significantly higher (p ~ 0.05) than that in untreated
(males, 0.22 :f 0.03; females, 0.17 :f 0.02) or vehicle-treated (males, 0.25 f: 0.05;

females, 0.23 :f 0.04) control mice. With lower doses, the increase in the number of lung tumours per mouse was not statistically significant (Stoner et al., 1973).

Groups of 35 male and 35 female B63F1 mice, 38 days of age, received

intraperitoneal injections of azcitidine at 2.2 or 4.4 mg/g bw (~99% pure) in buffered saline three times a week for 52 weeks. Groups of 15 male and 15 female
mice were untreated or recived the vehicle only. Survving mice were killed at 81 or

82 weeks. AlI high-dose females died before week 62, with no significant increase in
the incidence of any tumour; of the low-dose females, 17/35 survved untIl

termination of the experiment. Among males, 7/35 of the high-dose group and 13/35 of the low-dose group survved to the end of the study. The overall numbers of

survivors in untreated and vehicle-treated groups were 25/30 and 20/30,

respectively. ln female mice of the low-dose group, lymphocytic and granulocytic the haematopoietic system were observed in 17/29 animaIs examined histologically, at a highly significant incidence (p ~ 0.(01) compared with the
neoplasms of

vehicle-control group (0/14); 10 of the treated animaIs had granulocytic tumours

(nine sarcomas, one leukaemia). A malignant lymphocytic lymphoma was obseived in 1/15 untreated controls. No increase in the incidence of tumours was observed in male mice (National Cancer Institute, 1978). Groups of 50 male and 50 female BALB/c/Cb/Se mice, eight weeks of age, were given intraperitoneal injections of azacitidine at 2.0 mg/kg bw in saline (99% pure)

once a week for 50 weeks. Control groups received injections of saline. Mer 25
weeks, survival was reduced in exposed animaIs of each sexe The incidence of

lymphoreticular neoplasms was increased, occurring in 1250 (p ~ 0.01) males and 36/50 (p ~ 0.001) females, compared to 3/50 and 6/50 in control males and females, respectively. The incidence of lung adenomas was increased in treated males (27/50
versus 12/50 fp ~ 0.01 D but not in females. Mammary gland adenocarcinomas and

adenoacanthomas were found in 7/50 treated females and in none of the controls.
The incidence of skin - tumours was increased in treated animaIs of each sex, occurring in 3/50 treated males compared to 0/50 controls fp ~ 0.05) and in 7/50
treated females compared to 1/50 controls fp ~ 0.01, log rank test) (Cavaliere et al.,

1987). (The Working Group noted that adenocanthomas are not described as
mammary tumours in reference sources; see Turusov (1973, 1976).)
Rat: Two groups of 12 or 8 male Fischer rats, weighing 160-180 g, were given

intraperitoneal injections of azacitidine at 2.5 or 10 mglg bw (purity unspecified) in

saline twice a week for nine months. A control group of 12 male rats was maintained

without treatment. AlI rats were killed at 18 months. Interstitial-ceU testicular

AZACffDlNE
tumours were found in 1/8 high-dose animaIs

51

and 9/12 low-dose animals cmpared to 0/12 controis. ln the high-dose group, two squamous-cll carcinomas of the skin

and one skin appendage tumour at the site of injection were found, compared to
none in controls (Carr et al., 1984). (The Working Group noted the small number of animaIs tested, and the absence in controls of testicular tumours, which occurred commonly in a secnd, shorter study by the same investigators (sec below).)
Groups of 10, 10 or 100 young aduit male Fischer rats, weighing 100-160 g,

recived intraperitoneal injections of azacitidine at 0.025, 0.25 or 2.5 mg/kg bw in saline (purity unspeified) three times a week for one year. A control group of 50 rats was injected with saline. At one year, when the study was terminated, 87/100 of animaIs at the high dose and 10/10 in each of the lower-dose groups were still alive. The highest dose increased the incidence of testicular interstitiai-cell tumours to 56/87, compared to 10/49 in controls (p ~ 0.(01). No other tumour was observed in controis. ln the highest dose group, other tumours noted were four lymphomas, four renal tumours, one lung tumour, three skin tumours, two mesotheliomas and two sarcomas (Carr et al., 1988). (The Working Group noted the short duration of the experiment and the small numbers of animaIs in some groups.)
(h) Transplacental administration

Mouse: Groups of 32-37 pregnant NMI mice received intraperitoneal

injections of azacitidine at 1 or 2 mglg bw in saline (purity unspecified) on day 12, 14 or 16 of gestation. A group of 53 control dams was injected with saline. The number of stilbirths was increased at the high dose; survivai of offspring was

decreased in aIl expsed groups. ln exposed progeny, increased percentages of

tumour-bearing animaIs and increased incidences of Ieukaemias and lymphomas, lung tumours and liver tumours were seen in some groups (see Table 1). Some increases in the incidence of soft-tissue sarcomas were also seen (Schmahl et al.,
1985).

(c) Administration in comhination with other compounds Rat: ln the experiment by Carr et al. (1984), described above, groups of 6-10

male Fischer rats were given N-nitrosodiethylamine at 50 mglg bw 18 h after

partial hepatectomy, alone or with azacitidine at 2.5 or 10 mglg bw by

intraperitoneal injection. Liver tumours were found in 2/10 and 8/10 animaIs given the low and the high dose of azacitidine, respectively, but not in the group given the nitroso compound alone.

52

IARC MONOGRAHS VOLUM 50

Table 1. Incidences of tumours in the progeny of NMRI mice given azcitidineby intraperitoneal injectiontl
Treatment

Se
day of

No.

of

Leukaemias
and Iymphomas

Lung tumours
No.

rier tumours

animaIs

mgl bw
1

No.

gestation
12
12

No.

%
9.1 3.8

Males Females Males Females

165

15
113 110

81 80 28 26

49.1 50.6
24.8 23.6 23.6 15.2
9.3 13.9

30 33

18.2 20.9
19.5

15

6
11

2
1

22 22
29 31 46 43 81 99
78

20.0
16.3 18.1

9
12

9.7 8.2
6.7 11.7
11.3

14 14
16 16

Males
Fern ales

178 171

42 26
9
14

20
11

2
1

Males Females Males

Fern ales

97
101
153 160

47.4 42.6

7
14 8
18 5

6.9

97 98 67 57

63.4 61.3 42.4 37.7 28.7 29.4

529
61.9 49.3 54.3
19.5 19.0

9.2 5.0
11.4 3.3

2
Con troIs

Males
Fern ales

158 151

82
57 53

Males
Fern ales

293 279

84 82

14 11

4.8 3.9

aprorn Schrnahl et al. (1985)

3.2 Other relevant data

(a) Exerimental sytems
(i) Absorption, distriution, cxretion and metabolism

Blood levels of azacitidine, determined by biological activity, in mice peaked

within 0.5 h after intraperitonealor oral administration. Maxmal concentrations of

in blood 15 min after intraperitoneal injection of

azcitidine in blood after administration at 50 mglg bw were about 2 J.g/ml after oral administration and 43 l.g/ml after intraperitoneal injection (Neil et al., 1975). ln a study using a microbilogical assay, maxmal concentrations were found 9.5 and 4.75 mglg bw (LDio and

0.5 LDio) to mice. Elimination was rapid, and no azcitidine was detected in blood 1 h after injection of the high dose or 30 min after injection of the low dose. No drug

n, spleen or kidneys (Pittillo & Woolley, 1969). ln a further study, 14c activity in bloo diminished rapidly in mice after intraperitoneal administration of labelled azacitidine (Raska et al., 1965). The half-time for azacitidine and its radioactive metabolites was calculated by von Hoff and Slavic (1977) to be 3.8 h; radioactivity was retained in lymphatic organs.
was detected in liver, lung, brai

AZAcmDINE

53

As reported in an abstract, 50% of a dose (amount and route unspecified)

administered to mice was excreted in the urine within 8 h; of the excreted

radioactive material, 4% was associated with unchanged azacitidine. Six additional
radioactive metabolites were found (Coles et al., 1975). ln beagle dogs, azacitidine,

5-azacytosine, urea and guanidine were observed after intravenous administration

of azacitidine at 0.5 mg/kg bw; 33% of the administered dose was excreted in urine

by 4 h (Coles et al., 1974). ln rabbits, most of the radioactivity (25-40%) was excreted in the urine after intravenous administration of labelled azacitidine at 15 mg/kg bw; only small amounts were excreted via the bile (Chan et al., 1977). Azacitidine is phosphorylated and inhibits uridine kinase and orotidylic acid

hydroxylase (von Hoff et al., 1975, 1976). It is readily deaminated in biological

systems to 5-azauridine, which is degraded further (Cihk, 1974; Neil et al., 1975;

Glover & Leyland-Jones, 1987).

(ii) Toxic effects

As reported in an abstract, the intraperitoneal LDso for azacitidine in mice

was 116 mg/kg bw and the oral LDso, 572 mg; fIve daily doses increased the toxicity

considerably (Palm & Kensler, 1971).

After phosphorylation, azacitidine is incorporated into DNA and RNA in

L1210 leukaemia cells in vitro (Li et al., 1970); it inhibits DNA synthesis in the liver of
partially hepatectomized rats. Intraperitoneal injection of azacitidine at 10

lLmol/lOO g bw inhibited thymidine kinase and thymidylate kinase in rat liver (Cihk & Vesely, 1972). Azacitidine is cytotoxic to Friend eryhroleukaemia cells (Hickey et al., 1986), L1210 leukaemia cells (Li et al., 1970) and normal rat hepatocytes (Carr et aL., 1988) in vitro; after a dose of 1 X 10-4 M, 32% survival of rat hepatocytes was observed within 24 h.

(ii) Hypmethylation and effects on gene exression After incorporationinto DNA, azacitidine inhibits DNA methyl transferase
noncompetitively, blocking cytosine methylation in newly replicated DNA. Since

hypomethylation patterns in DNA are related to gene expression, this may be the mechanism by which azacytidine induces a range ofbiological effects (Glover et al.,

1987). A number of in-vitro and in-vivo studies have shown that azacitidine
treatment affects both differentiation (Constantinides et aL., 1978; Taylor & Jones,

1979; Tsao et al., 1984; Csordas & Schauenstein, 1986; Liu et al., 1986; Smat et al., 1986; Rothrock et al., 1988) and gene expression (Tennant et al., 1982; Harrison et al.,
1983; Rothrock et al., 1983; Sugiyama et al., 1983; deI Senno et al., 1984; Waalkes &

Poirier, 1985; Castelaz et al., 1986; Hickey et al., 1986; Hoshino et al., 1987;
Ishikawa et al., 1987; Price-Haughey et al., 1987; Carr et al., 1988; Stephanopoulos et al., 1988; Wagner et al., 1988).

54

IARC MONOGRAHS VOLUME 50

(iv) Effects on reproduction and prenatal toxicity

Intraperitoneal administration of azcitidine at 1.5-2.5 mg/kg bw to mice for

various periods during pregnancy induced very high or total resorption of

conceptuses when treatment was given in the preimplantation period up to day 6; after this time, the incidence of resorptions was only slightly greater than the control
level (Svata et al., 196; Seifertov et al., 1968). Other workers have shown that single intraperitoneal doses of 1-2 mg/kg to mice during the period of embryogenesis can cause a high resorption rate and malformations in the majority of surviving fetuses,

including major central nervous system defects, facial clefts and limb defects
(Schmahl et al., 1984; Takeuchi& Takeuchi, 1985).

Intraperitoneal injection of azcitidine at 1-4 mglg to mice at latet stages of pregnancy, especially on day 15, can result in morphological changes in the brain
(Langman & Shimada, 1971), and behavioural changes can be detected in offspring
when tested as adults (Rodier et al., 1973; Langman et al., 1975; Rodier, 1979).

The primary mechanism by which azacitidine causes malformations in rats is thought to be induction of cell death, but inhibition of some but not all of the effects
of azacitidine by administration of caffeine indicates that more th

an one

mechanism may be involved (Kurishita & Ihara, 1987a,b).

(v) Genetic and related effects ln Escherichia coli, azcitidine caused DNA damage (Bhagwat & Roberts,
1987) and prophage induction (Barbe et aL., 1986). It was mutagenic to E. coli (Fucik
et al., 1965; LaI et al., 1988) and induced base-pair but not frameshift mutations in

Salmonella tyhimurium (Marquardt & Marquardt, 1977; Podger, 1983; CalI et al., 1986; Levin & Ames, 1986; Schmuck et al., 1986). Azacitidine induced mitotic recombinations, mitotic gene conversions and reverse mutations but not mitotic chromosome loss in Saccharomyces cerevisiae
(Zimmermann & Scheel, 1984). It induced mitotic recmbinations, deletions and gene mutations in the wing spot assay in Drosophila melanogaster (Katz, 1985) and chromosomal aberrations in root meristem cells of Vicia laba (Fucik et al., 1970).

Azcitidine inhibited DNA synthesis in Chinese hamster CHO cells (Tobey, 1972) and induced DNA strand breaks in HeLa cells (Snyder & Lachmann, 1989).
It induced mutations at the hprt locus in Chinese hamster V79 cells iD one study (at

5 l1M; Marquardt & Marquardt, 1977) but not in another (at 40 l1M; Landolph & Jones, 1982). It did not iDduce mutation at the hprt locus in Syrian hamster BHK cells (Bouck et al., 1984), primary rat tracheal epithelial cells (Walker & Nettesheim,

1986) or mouse lymphoma 15178Y cells (at 4 l1M; McGregor et al., 1989).
Azacitidine induced mutations at the hprt and tk loci in human fibroblasts (CalI et al., 1986) and at thetk locus of mouse lymphoma 15178Y cells (Amacher & Turner, 1987; McGregor et al., 1989). It did not induce ouabain-resistant mutations in

AZAcrnDINE

55

mouse C3H 10T1f, Chinese hamster V79 (Landolph & Jones, 1982), Syrian hamster

BHK (Bouck et al., 1984) or primary rat tracheal epithelial cells (Walker &
Nettesheim, 1986).

lymphoces (up to 9 J.M; loannidou et al., 1989). It induced chromos

aberrations in Chinese hamster Don cells (Karon & Benedict, 1972) and in hum

Azcitidine induced sister chromatid exchange in a cloned hamster cell line (Banerjee & Benedict, 1979), inCHO cells (Hori, 1983) and in human peripheral lymphoces in vitro (only one concentration, 8 J.M, was tested) (Lavia et al., 1985). an omal an
ln another study, azcitidine did not induce sister chromatid exchange in hum

peripheral lymphocytes in vitro (only one concentration, 8 J.M, was tested) (Lavia et
al., 1985) but not in hum

an lymphoblasts (10 J.M; Call et al., 1986).

Azcitidine induced transformation in mouse C3H110rh (Benedict et al.,

1977), Syrian hamster BHK (Bouck et al., 1984), mouse BALB/313 (Yasutake et al., 1987) and primary rat tracheal epithelial cells (Walker & Nettesheim, 1986).

Azacitidine did not induce dominant lethal mutation in male mice after
administration at 5 and 10 mglg bw intraperitoneally (Epstein et al., 1972).
(h) Humans

The toxicity, cytostatic activity and mechanism of action of azacitidine have

been reviewed (Cihk, 1974; von Hoff & Slavik, 1977; Glover & Leyland-Jones,
1987).
(i) Pharmcokinetics

Afer an intravenous injection of radiolabelled azacitidine, the ~-phase half-time of radioactivity was 16-33 min (Israeli et al., 1976), and the -phase
half-time was 3.4-6.2 h (Troetel et al., 1972; Israeli et al., 1976). Afer 30 min, less th

2% of the plasma radioactivity cohromatographed with azcitidine; at least two different metabolites or decmposition products were detected by thin-Iayer chromatography (Israeli et al., 1976), and 73-98% of the injected radioactivity was

an

detected in the urine within three days (Israeli et al., 1976). Similar results were
obtained by Troetel et al. (1972).

Less than 1% of radiolabelled azacitidine was bound to human serum albumin

in vitro (Israeli et al., 1976).

(ii) Adverse effects

The major toxic. effects of the clinical use of azcitidine have been
gastrointestinal, haematological and hepatic (von

Hoff et al., 1976; von Hoff &

Slavik, 1977; Reynolds, 1989). Leukopenia is generally the dose-limiting toxicity; in

a compilation of several studies with a total of 821 patients, the incidence of

leukopenia (total leukoce count, less than 1500/mm3) was 34% and was
dose-related. Thromboopenia has ben reported less frequently (von Hoff et al.,

56

IARC MONOGRAHS VOLUME 50

1976; von Hoff & Slavik, 1977). Fatal hepatic damage was reported in four patients

with previous hepatic dysfunction, who had ben treated with azcitidine (Bellet et
al., 1973).
(ii) Effects on reproduction and prenatal toxicity

No data were avaIlable to the Working Group.

(iv) Genetic and related effects No adequate study was avaIlable to the Working Group.
3.3 Case reports and epidemiological studies of carcinogenicity to humans
No data were avaIlable to the Working Group.

4. Summary of Data Reported and Evaluation

4.1 Exposure data

Azacitidine is a cytostatic agent that has been used since the 1970s for the
treatment of acute leukaemia.

4.2 Experimental carcinogenicity data

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. ln one study in mice, it accclerated the development of leukaemias; in
the two long-term studies and in the transplacental study, it increased the incidence

of lymphoid neoplasms. ln 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 sexe ln the transplacental study in mice, it also increasrd the incidences oflung and liver tumours. It accelerated the induction of lung tumours in mice. ln rats, it increased the incidence of testicular tumours.

Intraperitoneal administration of azacitidine to rats enhanced the

development of liver tumours induced by N-nitrosodiethylamine.
4.3 H uman carcinogenicity data
No data were avaIlable to the Working Group.
4.4 Other relevant data

During the early stages of gestation, azcitidine induces embryomortality in mice; during the organogenesis period, multiple, gross structural malformations

AZAClllNE
defects have been induced in mice.

57

can be induced; and during later stages of gestation, mainly central nervous system

Azcitidine is readily deamInated to azuridine and further degraded. It is

incorporated into DNA and alters gene expression. ln humans, it causes

leukopenia. Azcitidine causes hypmethylation of DNA both in vivo and in vitro. ln one study, azacitidine did not induce dominant lethal mutations in mice.

Contradictory results have ben reported with respet to the induction of

chromosomal aberrations and sister chromatid exchange in human cells. ln single

studies, azcitidine induced gene mutations and DNA strand breaks in human ter 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 recmbination and mutations in Drosophila. Azacitidine Induced chromosomal aberrations in Vicia loba. ln Saccharomyces cerevisiae, it induced gene mutations and mitotic recmbination but not chromosomal loss. It induced
cells. It induced chromosomal aberrations in Chinese hamster cells, sis

mutations and DNA damage in Salmonella tyhimurium and Escherichia coli. (See Appendix 1.)
4.5 Evaluation1

There is suffcient evidence for the carcinogenicity of azacitidine in

experimental animaIs.

ans on the carcinogenicity of azacitidine. ln making the overall evaluation, the Working Group also took note of the
No data were available from studies in hum

following information. Azcitidine is active in a broad spectrum of assays for

genetic and related effects, including those involving mammalian cells. Furthermore, azcitidine, a pyrimidine analogue, is incorporated into DNA, causing hypmethylation.
Overall evaluation

Azacitidine is probably carcinogenic to humons (Group lA).

1Por desription of the italicize terms, se Preamble, pp. 2629.

58

IAC MONOGRAHS VOLUM 50

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Amacher, D.E. & Ther, G.N. (1987) The mutagenicity of 5-azcyidine and other inhibitors of replicative DNA sythesis in the L5178Y mouse lyrphoma celle Mutai. Re., 176,
123-131

Banerjee, A. & Benedict, W:F. (197) Production of siSter ehromatid exehanges by varous

cacer ehemotherapeutic agents. Caner Re., 39, 79-79

Barbe, J., Gilbert, 1. & Guerrero, R. (1986) 5-Azcyidine: suival and induction of the SOS
respnse in Eseheriehia coli K12. Mutai. Re., 166, 9-16 Beisler, J. (1978) Isolation, eharacterition, and properties of a labile hydrolysis product of

the antitumor nucleoside 5-azcyidie. L me. Che., 21, 20-20

Bellet, R.E., Mastragelo, MJ., Engstrom, :PE & Custer, R.:P (1973) Hepatotoxicity of 5-azcyidine (NSC-102816) (A elica and pathologie study). Neoplas, 20, 303-30 Benedict, W:F., Banerjee, A., Gardner, A. & Jones, :PA. (1977) Induction of morphological transformation in mouse C3HIlOTlh clone 8 cells and chromosomal damage in hamster

A(fi)CI-3 cells by cancer chemotherapeutic agents. Caner Re., 37,2202-2208 Bhagwat, AS. & Roberts, RJ. (1987) Genetic analysis of the 5-azcyidine sensitivity of Escherichia coli K-12.1 Bateriol., 169, 1537-154 Bouek, N., Kokiaki, D. & Ostrowsky, J. (1984) Induction of a step in carciogenesis that is
normally assted with mutagenesis by nonmutagenie concentrations of
5-azcyidine. Mol. Cell Biol., 4, 1231-1237

CalI, K.M., Jensen, J.C., LIber, H.L. & Thily, W:G. (1986) Studies of mutagenicity and clastogenicity of 5-azcyidine in human lyrphoblasts and Salmonella tymurium.
Mutai. Re., 160, 249-257

Carr, B.I., Reily, J.G., Smith, S.S., Winberg, C. & Riggs, A. (1984) The tumorigenicity of
5-azcyidine in the male Fisher rat. Carcinogeneis, 5, 1583-1590

Carr, B.I.,Rahbar, S., Asmeron, Y., Riggs, A & Winberg, C.D. (1988) Carcinogenicity and

haemoglobin sythesis induction by cyidine analogues. Br L Caner, 57, 395

Castellazi, M., Vielh, P. & Longacre, S. (1986) Azcyidine-induce reactivation of

adenosine deaminase in a murie cyotoxie T cell line. Eur. L Immnol., 16, 1081-1086 Cavaliere, A, Bufalari A & Vitali, R. (1987) 5-Azcyidine carcinogenesis in Balb/e mice.
Caner Lett., 37, 51-58

Chan, K.K., Starosc, J.A. & Sade, W. (1977) Synthesis of 5-azcyidine-6-C and 6_14C.L med. Chem., 20,598-60
Chemical Information Semces (1989-90) Direetory ofWorld Chemical Producers, Oeeanside,

NY
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