Nonclinical Toxicology Studies with Zidovudine: Genetic Toxicity Tests and Carcinogenicity Bioassays in Mice and Rats

Ayers, K. M.

doi:10.1006/faat.1996.0118

Cited by 100 publications

(29 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to Viread's Product Monograph, gastrointestinal tumorigenicity has been observed in mice after high oral dosing of tenofovir disoproxil fumarate. Vaginal tumorigenicity has been documented for azido-thymidine, an NRTI and DNA chain terminator like tenofovir, which induced vaginal hyperplasia and carcinomas when delivered to mice intravaginally as a 2% solution (~25% carcinoma rate) 52 .…”

Section: Figure 5 Quantification Of Mitochondriaassociated Parametersmentioning

confidence: 99%

Mucosal effects of tenofovir 1% gel

Hladik

Burgener

Ballweber

et al. 2014

Preprint

View full text Add to dashboard Cite

BACKGROUND Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa. METHODS AND FINDINGS In MTN-007, a phase 1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. After seven days of administration, tenofovir 1% gel had broad-ranging biological effects on the rectal mucosa, which were much more pronounced than—but different from—those caused by the detergent nonoxynol-9. Tenofovir profoundly suppressed anti-inflammatory mediators such as interleukin 10; increased T cell densities; caused mitochondrial dysfunction, possibly by blocking PNPT1 expression; and altered regulatory pathways of cell differentiation and survival. Except for leukocyte-derived factors, all these effects were replicated in primary vaginal epithelial cells, which also proliferated significantly faster in tenofovir’s presence. CONCLUSIONS Tenofovir’s suppression of anti-inflammatory activity could diminish its prophylactic efficacy over time. The breadth of mucosal changes, including mitochondrial dysfunction and epithelial proliferation, raises questions about its safety for long-term topical use. These findings suggest that a systems biology evaluation of mucosal effects may be beneficial before advancing to large-scale efficacy trials with topical HIV prevention agents that achieve high, long-lasting local drug concentrations.

show abstract

Section: Figure 5 Quantification Of Mitochondriaassociated Parametersmentioning

confidence: 99%

Mucosal effects of tenofovir 1% gel

Hladik

Burgener

Ballweber

et al. 2014

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, HIV-uninfected infants born to mothers with HIV may be exposed to ZDV both transplacentally during gestation, and directly during the postpartum treatment period. Although ZDV is tremendously effective in preventing vertical transmission of HIV, ZDV has been shown to be carcinogenic in animals (Ayers et al, 1996;National Toxicology Program, 1999Olivero et al, 1997;Diwan et al, 1999), genotoxic in numerous in vitro and in vivo test systems (Phillips et al, 1991;Sussman et al, 1999;Poirier et al, 2004;Chan et al, in press;von Tungeln et al, 2004;Meng et al, 2002), and incorporated into DNA of primates and humans after transplacental or direct exposure (Poirier et al, 2004Olivero et al, 2000Olivero et al, ,2002.…”

Section: Introductionmentioning

confidence: 99%

Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother‐to‐child transmission of HIV

Witt

Cunningham

Patterson

et al. 2007

Environ and Mol Mutagen

View full text Add to dashboard Cite

Zidovudine-based antiretroviral therapies (ART) for treatment of HIV-infected pregnant women have markedly reduced mother-to-child transmission of the human immunodeficiency virus (HIV-1) from ~25% to <1%. However, zidovudine (ZDV; AZT), a nucleoside analogue, induces chromosomal damage, gene mutations, and cancer in animals following direct or transplacental exposures. To determine if chromosomal damage is induced by ZDV in infants exposed transplacentally, we evaluated micronucleated reticulocyte frequencies (%MN-RET) in 16 HIVinfected ART-treated mother-infant pairs. Thirteen women received prenatal ART containing ZDV; 3 received ART without ZDV. All infants received ZDV for 6 weeks postpartum. Venous blood was obtained from women at delivery, and from infants at 1-3 days, 4-6 weeks, and 4-6 months of life; cord blood was collected immediately after delivery. Ten cord blood samples (controls) were obtained from infants of HIV-uninfected women who did not receive ART. %MN-RET was measured using a single laser 3-color flow cytometric system. Ten-fold increases in %MN-RET were seen in women and infants who received ZDV-containing ART prenatally; no increases were detected in 3 women and infants who received prenatal ART without ZDV. Specifically, mean %MN-RET in cord blood of ZDV-exposed infants was 1.67±0.34 compared with 0.16±0.06 in non-ZDV ARTexposed infants (P=0.006) and 0.12±0.02 in control cord bloods (p<0.0001). %MN-RET in ZDVexposed newborns decreased over the first 6 months of life to levels comparable to cord blood controls. These results demonstrate that transplacental ZDV exposure is genotoxic in humans. Longterm monitoring of HIV-uninfected ZDV-exposed infants is recommended to ensure their continued health.

show abstract

“…Such tumors, while rare, do occur spontaneously. Since this animal was given ZDV for only 90 days postweaning, and we have shown that ZDV-related vaginal tumors occur only after at least 19 months of daily oral dosing (Ayers et al, 1996), it is likely that this single occurrence was of spontaneous origin.…”

Section: Resultsmentioning

confidence: 96%

“…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 or 40 mg/kg/day and after 24 months of dosing in rats given 300 mg/kg/day. The transplacental carcinogenicity study described here was conducted to determine if lifetime exposure to ZDV, beginning perinatally, would alter this pattern of carcinogenicity.…”

Section: Zidovudine (Zdv)mentioning

confidence: 99%

A Transplacental Carcinogenicity Bioassay in CD-1 Mice with Zidovudine

Ayers¹,

Torrey²,

Reynolds³

1997

Toxicol Sci

View full text Add to dashboard Cite

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 ...

show abstract

Nonclinical Toxicology Studies with Zidovudine: Genetic Toxicity Tests and Carcinogenicity Bioassays in Mice and Rats

Cited by 100 publications

References 11 publications

Mucosal effects of tenofovir 1% gel

Mucosal effects of tenofovir 1% gel

Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother‐to‐child transmission of HIV

A Transplacental Carcinogenicity Bioassay in CD-1 Mice with Zidovudine

Contact Info

Product

Resources

About