Portal de Periódicos da CAPES

AZT IS A GENOTOXIC TRANSPLACENTAL CARCINOGEN IN ANIMAL MODELS

1997; Lippincott Williams & Wilkins; Volume: 14; Issue: 4 Linguagem: Inglês

10.1097/00042560-199704010-00093

2331-6993

Ofelia A. Olivero, Lucy M. Anderson, Bhalchandra A. Diwan, Diana C. Haines, Charles W. Riggs, Thomas J. Moskal, Ann B. Jones, James Mahmud Rice, Stuart H. Yuspa, Miriam C. Poirier,

Nutrition, Genetics, and Disease

Background: In HIV-1-positive pregnant women, 500 mg AZT given daily in multiple doses for the last two trimesters reduces the maternal-fetal virus transmission rate to∼7% from ∼25%, effectively protecting about 1300 children a year in the United States. However, in adult mice lifetime AZT administration induces vaginal tumors at a 10-20% incidence. Here we present studies designed to investigate fetal monkey and mouse genotoxicity and mouse tumorigenicity in offspring exposed to AZT during gestation. Methods: Pregnant patas monkeys were given 10 mg AZT daily (equivalent to 100 mg in a pregnant woman) during the last half of gestation. Multiple fetal tissues were examined at term for incorporation of AZT into DNA by anti-AZT-radioimmunoassay(RIA). Pregnant CD-1 mice were given daily doses of 12.5 mg and 25.0 mg AZT by gavage for the last 7 days (30%) of gestation. Some pups were examined at birth for AZT-DNA incorporation (by RIA) and telomere length (Southern blot, hybridization with a telomeric probe), and others were sacrificed and examined for tumors at 1 year. Results: In newborn monkeys and mice, AZT was incorporated into DNA of many fetal tissues, including liver and lung. AZT-DNA levels were higher in the monkey despite the lower dose. Some mouse litters also sustained a shortening of telomeres in liver, brain and lung. At the 25 mg dose, tumor incidences in lungs of both males and females and livers of males were 3- to 8-fold higher than in the controls. In female reproductive organs the controls had no tumors, and there was a 17% incidence of ovarian and uterine tumors at the 25 mg dose. Conclusions: Compared to other known chemical carcinogens, AZT appears to be a moderately-strong transplacental carcinogen. AZT-DNA incorporation into multiple fetal tissues of both monkeys and mice suggests that genotoxic damage may play a role in tumor initiation. The biological consequences of shortened telomeres are presently unknown. Whereas the daily mouse doses (∼500 mg AZT/kg body weight) were much higher than those given to women (∼8 mg AZT/kg body weight) the total mouse doses were similar to those given to women who take the drug for 6 months. The data suggest that surveillance of AZT-exposed children should be carried out well into adulthood.