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Abstract for GMM-14

Toxicology and Carcinogenicity Studies of 3´-Azido-3´-Deoxythymidine (AZT) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study)

CASRN: 30516-87-1
Chemical Formula: C10H13N5O4
Molecular Weight: 267.24
Synonyms/Common Names: AZT; 3´-azido-2´,3´-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3´-azidothymidine; 3´-deoxy-3´-azidothymidine; 3´-deoxy-(8CI) (9CI); BW A509U; Compound S; ZDV; zidovudine
Report Date: October 2013

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Abstract

Antiviral therapy is essential for treatment and prevention of human immunodeficiency virus (HIV) disease in adults and children and to prevent mother-to-child transmission of HIV during pregnancy and labor. The studies described in this report were designed to determine possible long-term sequelae from 3´-azido-3´-deoxythymidine (AZT) treatment, often used in combination with other antivirals, in preventing mother-to-child transmission of HIV. AZT is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS).

Male and female heterozygous F1 p53+/– mice were exposed, by maternal gavage, to AZT in utero on gestation days (GD) 12 through 18, then administered AZT by gavage from postnatal day (PND) 1 through 30 weeks of age (30-week study), 45 weeks of age (45-week study), or PND 8 (45-week stop-study). Mice in the 0 mg/kg groups received only an aqueous solution containing 0.2% methylcellulose and 0.1% Tween® 80. Mice were dosed once daily until PND 28, then 5 days per week. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes.

30-Week Study

Pregnant dams were administered 0 or 240 mg AZT/kg body weight per day on GDs 12 through 18. Groups of 26 or 27 male and 26 or 27 female pups were administered 0 or 120 mg/kg by gavage on PNDs 1 through 10, then 0 or 240 mg/kg until the end of the study. Survival of 240/120/240 mg/kg males was significantly less than that of 0/0/0 mg/kg males. Mean body weights of dosed males and females were less than those of the 0/0/0 mg/kg groups, and absolute kidney weights of dosed males and females were significantly less than those of the 0/0/0 mg/kg groups. Mean cell volume and mean cell hemoglobin in dosed females and mean cell volume in dosed males were significantly increased, suggesting moderately severe macrocytic anemia.

The incidence of malignant lymphoma was increased in male mice administered 240/120/240 mg/kg. The increase was significant when adjusted for litter correlations.

45-Week Study

Pregnant dams were administered 0, 80, 160, or 240 mg/kg on GDs 12 through 18. Corresponding groups of 27 male and 26 or 27 female pups were administered 0, 40, 80, or 120 mg/kg on PNDs 1 through 10, then 0, 80, 160, or 240 mg/kg until the end of the study. There was no effect of AZT administration on the survival of dosed mice. Mean body weights of dosed males and females were generally less than those of the 0/0/0 mg/kg groups. Absolute brain weights of males and females administered 240/120/240 mg/kg were significantly less than those of the 0/0/0 mg/kg groups. Mean cell volume and mean cell hemoglobin at 160 days were increased in 240/120/240 mg/kg males and females, suggesting moderately severe macrocytic anemia.

The incidences of hepatocellular adenoma occurred with a positive trend in males, and the incidence in the 240/120/240 mg/kg group was significantly increased. In females, there was a positive trend in the incidences of malignant lymphoma, and the increased incidence in the 240/120/240 mg/kg group was significant when adjusted for litter correlations.

45-Week Stop-Study

Pregnant dams were administered 0 or 240 mg/kg on GDs 12 through 18. Groups of 24 or 25 male and 26 female pups were administered 0 or 40 mg/kg on PNDs 1 through 8; pups were then maintained on study until 45 weeks of age without dosing. There was no effect of AZT administration on the survival of dosed mice. Mean body weights of dosed males were generally less than those of the 0/0 mg/kg group. Absolute, but not relative, brain weights of dosed males and females were significantly less than those of the 0/0 mg/kg groups. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were slightly increased in 240/40 mg/kg males.

Genetic Toxicology

Micronucleated normochromatic erythrocytes and reticulocyte frequencies were generally significantly increased relative to the corresponding 0, 0/0, or 0/0/0 mg/kg group values in 1-day-old pups exposed to AZT in utero at 160 or 240 mg/kg, in 10-day-old pups administered 80/40, 160/80, or 240/120 mg/kg, in 28-day-old pups administered 80/40/80, 160/80/160, or 240/120/240 mg/kg, and in 30-week-old mice administered 240/120/240 mg/kg.

Conclusions

Under the conditions of these gavage studies, there was clear evidence of carcinogenic activity of of AZT in male heterozygous F1 p53+/– mice based on the occurrence of hepatocellular neoplasms (predominantly adenomas) after 45 weeks of administration. The occurrence of malignant lymphoma may have been related to AZT administration for 30 weeks. There was equivocal evidence of carcinogenic activity of AZT in female heterozygous F1 p53+/– mice based on the occurrence of malignant lymphoma after 45 weeks of administration.

Studies

Summary of the In Utero/Postnatal Gavage Studies of AZT in C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice
  Male Female
Doses in aqueous methylcellulose/Tween® 80 by gavage
30-Week Study[a] F0: 0 or 240 mg/kg per day
F1: 0 or 120/240 mg/kg per day
F0: 0 or 240 mg/kg per day
F1: 0 or 120/240 mg/kg per day
45-Week Study[a] F0: 0, 80, 160, or 240 mg/kg per day
F1: 0, 40/80, 80/160, or 120/240 mg/kg per day
F0: 0, 80, 160, or 240 mg/kg per day
F1: 0, 40/80, 80/160, or 120/240 mg/kg per day
45-Week Stop-Study F0: 0 or 240 mg/kg per day
F1: 0 or 40 mg/kg per day postnatal days 1-8
F0: 0 or 240 mg/kg per day
F1: 0 or 40 mg/kg per day postnatal days 1-8
Body weights Dosed groups less than 0 mg/kg groups Dosed groups less than 0 mg/kg groups, except in 45-week stop-study
Survival rates
30-Week Study
45-Week Study
45-Week Stop-Study


27/27, 21/26
24/27, 21/27, 27/27, 22/27
23/24, 22/25


24/27, 26/26
23/26, 23/27, 24/27, 21/27
25/26, 23/26
Nonneoplastic effects
30-Week Study
45-Week Study
45-Week Stop-Study


None
None
None


None
None
None
Neoplastic effects
30-Week Study
45-Week Study
45-Week Stop-Study


None
Liver: hepatocellular adenoma (3/26, 2/27, 6/27, 9/27)
Liver: hepatocelluar adenoma (3/24, 5/25); hepatocellular adenoma or carcinoma (3/24, 7/25)


None

None
None
Equivocal findings
30-Week Study
45-Week Study
45-Week Stop-Study


Malignant lymphoma: (0/27, 3/26)
None
None


None
Malignant lymphoma: (0/26, 0/27, 1/27, 3/27)
None
Level of evidence of carcinogenic activity Clear evidence Equivocal evidence
Genetic toxicology

Micronucleated normochromatic erythrocytes and reticulocytes

 

30-Week Study
45-Week Study
 
Positive in males and females at 30 weeks of age
Positive in males and females at PND 1, PND 10, and PND 28

[a]Pups in the 30- and 45-week studies were administered AZT doses that were half that of the maternal dose on post natal days 1 through 10.

 Pup doses were the same as maternal doses from post natal day 11 until the end of the studies.