Toxicology and carcinogenesis of 3´-azido-3´-deoxythymidine (AZT) (CAS No. 30516-87-1) in genetically modified C3B6.129F1-Trp53(tm1Brd) N12 haploinsufficient mice (in utero and postnatal gavage studies).

Unlabelled: 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. Synonyms: AZT; 3´-azido-2´,3´-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3´-azidothymidine; 3´-deoxy-3´-azidothymidine; 3´-deoxy-(8CI) (9CI); BW A509U; Compound S; ZDV; zidovudine Trade Name: Retrovir®