National Toxicology Program genetically modified model report最新文献

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,

Unlabelled: 3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS). Antiviral therapy is essential for treatment and prevention of AIDS in adults and children infected with human immunodeficiency virus (HIV), 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 AZT treatment, often used in combination with other antiviral drugs, such as lamivudine (3TC) and nevirapine (NVP) in preventing mother-to-child transmission of HIV. Male and female heterozygous F1 p53+/- mice were exposed to AZT, 3TC, NVP, or combinations of the chemicals in utero on gestation days (GD) 12 through 18, then administered the same chemical or combination of chemicals by gavage from postnatal day (PND) 1 through PND 28 and then observed until 45 weeks of age. Vehicle control mice received only an aqueous solution containing 0.2% methylcellulose and 0.1% Tween 80. Mice were dosed twice daily until PND 28. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. The study compared three combination doses of AZT, 3TC and NVP (AZT/3TC/NVP-L, AZT/3TC/NVP-M, and AZT/3TC/NVP-H) with the vehicle controls, and compared the individual components with each other at the highest dose (AZT-H, 3TC-H, NVP-H, AZT/3TC-H and AZT/3TC/NVP-H). Because exposure to AZT/3TC/NVP-M and AZT/3TC/NVP-H reduced pup survival, additional litters were required to provide sufficient pups to load the 45-week study. 45-WEEK STUDY: In general, survival was relatively high once the pup exposure phase had been completed, with at least 75% of the mice surviving to terminal sacrifice in all groups. For males, survival was significantly greater in the AZT/3TC/NVP-L and AZT/3TC/NVP-M groups relative to the vehicle control group. There were no significant differences in survival between high dose groups of the constituent chemicals in either sex; however, survival of females in the AZT/3TC-H group was significantly less than that in the vehicle control group. Early deaths were predominantly associated with occurrences of malignant lymphoma, mammary gland tumors, and osteosarcomas. In the combination dose comparison, males and females dosed with the AZT/3TC/NVP-H combination had significantly decreased body weights compared to the vehicle control groups from PND 11 when individual monitoring began until 20 (males) or 11 (females) weeks. In addition, mean body weights for the male and female AZT/3TC/NVP-M groups were significantly less than those of the vehicle control groups until 14 weeks. In the high dose comparison, mean body weights of the male and female AZT-H groups were significantly less than those of the vehicle control groups during some of the early weeks of dosing. In male and female mice, absolute brain weights of the combination