A Transplacental Carcinogenicity Bioassay in CD-1 Mice with Zidovudine

Abstract

In oral carcinogenicity bioassays, zidovudine (ZDV) induced vaginal epithelial cell tumors in mice given 30 or 40 mg/kg/day and rats given 300 mg/kg/day. To determine if lifetime exposure to ZDV, beginning perinatally, would alter this pattern of carcinogenicity, two groups of 60 pregnant CD-I mice were given 20 or 40 mg/kg/day of ZDV in 0.5% methyl cellulose from Gestation Day 10 through Lactation Day 21. At weaning, 2 pups per sex from each of 35 litters in each group were assigned to the study and given 20 or 40 mg/kg/day of ZDV in the drinking water until 17-35 days of age, followed by daily gavage for 24 months. Two additional groups of 60 pregnant CD-I mice each were given 40 mg/kg/day of ZDV daily from Gestation Day 10 through Lactation Day 21; in one, ZDV treatment was halted at weaning and in the other, treatment was stopped 90 days after weaning. Two other groups of 60 pregnant CD-I mice were left untreated (environmental control) or were given 0.5% methyl cellulose beginning on Gestation Day 10 (vehicle control). Vehicle control progeny received plain drinking water for 17-35 days postweaning and then 0.5% methyl cellulose daily by gavage for 24 months. ZDV treatment did not affect survival or body weight in either sex. In females given 20 or 40 mg/kg/day of ZDV for 24 months there was mild macrocytic anemia. Similar, non-dose-related changes were seen in males in these groups. ZDV-related tumor findings were limited to the vagina, where there were 2 and 11 vaginal squamous cell carcinomas in mice given 20 or 40 mg/kg/day of ZDV daily, respectively. This incidence was not remarkably different from that seen in previously reported bioassays. It was concluded that lifetime oral treatment of mice with ZDV, beginning perinatally, did not alter the previously reported pattern of carcinogenicity and that under the conditions tested ZDV was not a transplacental carcinogen. t > 1997 soday of Toxicology. Zidovudine (ZDV)1 was the first antiviral agent licensed for the treatment of acquired immunodeficiency syndrome and has been used in adults and children since 1987. A placebo-controlled trial showed that treatment with ZDV 1 Zidovudine (3'-azido-3'-deoxythymidine) has previously been called AZT and azidothymidine. Retrovir is the tradename for ZDV.dramatically reduced the rate of transmission of HIV from mother to infant (Connor et al, 1995) and ZDV is now also approved for use in the prevention of maternal:fetal HIV transmission. The treatment regimen (Physicians ' Desk Reference, 1996) includes oral ZDV beginning between 14 and 34 weeks of gestation (100 mg po five times daily until the start of labor), iv ZDV during labor (2 mg/kg iv for 1 hr, then 1 mg/kg/hr iv until clamping of umbilical cord), and administration of ZDV to the newborn after birth (2 mg/kg po every 6 hr, continuing through 6 weeks of age).In oral carcinogenicity bioassays (Ayers et al., 1996), ZDV treatment, begun when animals were 42 days of age, was shown to induce vaginal epithelial cell tumors in mice after 22 months of dosing at 30 ...

Noise-induced hearing loss in mice treated with antiretroviral drugs

“…However, it was noted that the experimental mice were visibly thinner than the control mice, but this weight loss did not seem to be due to a lack of water consumption. In mouse studies, these drugs are frequently given orally, usually by gavage, but they can also be given in the drinking water (e.g., Ayers et al 1997;Note et al 2003). We chose the drinking-water approach, because of the ease of administration over the long 3-mo time frame.…”

Genotoxicity assessed by the comet and GPA assays following in vitro exposure of human lymphoblastoid cells (H9) or perinatal exposure of mother–child pairs to AZT or AZT‐3TC

“…The underlying mechanism is presumed to be AZT-DNA incorporation, which has been demonstrated in cultured cells, adult mice, and transplacentally exposed mouse, monkey, and human fetuses [IARC, 2000;Poirier et al, 2004]. Two-year carcinogenicity studies in adult rodents have shown that daily AZT exposure causes low-level increased incidences of vaginal tumors [Ayers et al, 1996[Ayers et al, , 1997. In addition, enhanced tumorigenicity was observed in multiple organs of mice and rats exposed transplacentally to AZT and grown to adulthood with no other exposures [Olivero et al, 1997;Zhang et al, 1998;Diwan et al, 1999;Walker et al, 2007.].…”

Skin tumorigenesis and Ki-ras and Ha-ras mutations in tumors from adult mice exposed in utero to 3′-azido-2′,3′-dideoxythymidine

“…At 1 yr of age, the tumor incidences were twofold to eightfold higher in the AZT-exposed mice than in the unexposed controls. The offspring of pregnant CD-1 mice given about 25-fold lower daily AZT doses did not show an AZTrelated increase in tumor incidence [8].…”

“…However, adult female mice given AZT orally develop vaginal squamous papillomas and carcinomas after a lifetime of exposure to AZT [4,5], and similar dosing of adult female mice with AZT for 28 d produces dose-related incorporation of the drug into vaginal DNA [6]. The long-term effects of transplacental AZT exposure have been studied in CD-1 mice [7,8]. Increased numbers of lung tumors in male and female mice, liver tumors in male mice, and female reproductive-organ tumors were observed in the offspring of mice exposed during pregnancy to daily doses of 12.5 mg or 25 mg of AZT for the last 7 d of gestation.…”