[醫(yī)藥衛(wèi)生]藥物的致癌性(參考版)
2025-04-17 00:34本頁(yè)面
【正文】 the average number used by species/strain/gender was in excess of 750 animals Preclinical approaches for assessing carcinogenic potential Tumorigenicity in humans, nonhuman primates and rodents Spontaneous tumor rates in the breeder and control animals The Neonatal Mouse Pietra et al. (1959). The neonatal mouse is one of the alternative in vivo models, for detecting the carcinogenic potential of pharmaceuticals. This is in agreement with the suggestions of ICH, which allows the use of one alternative study in place of one of the 2year carcinogenicity studies. When treatment begins within the first 24 hours of life, the study design is described as “newbornmouse”. “neonatal mouse” includes test item administration at different timepoints from birth to three weeks of age. Fujii (1991) reported that the neonatal mouse assay showed a sensitivity of 85% and a positive prediction rate of 96% pared to the results of the adult mouse 2year carcinogenicity study. Flammang et al. (1997) considered this model to have high sensitivity and specificity to detect genotoxic carcinogens as well as presenting advantages such as reduced test article requirements, decreased animal numbers and costs and a reduced pletion time. It does not respond to chemicals acting via epigeic mechanisms. McClain et al. (2022) reported that neonatal mice have been shown to have a reduced time for tumor induction, a higher multiplicity of induced tumors, a lower spontaneous tumor rate and an equivalent or higher sensitivity to carcinogens when pared to adult mice. This model also responds to a wide range of structurally dissimilar genotoxic pounds. Additionally, the neonatal mouse possesses the majority of the phase I and II biotransformation liver enzymes involved in the processes of activation and detoxification of carcinogens from different chemical classes. CD1 mice 10 to 12 weeks of age. Mice were caged with 5 females per male and examined each day for the presence of a vaginal copulation plug. Females were isolated until delivery, 6 litters with 4 neonates /sex/ litter were assigned to each group during the first week after birth. Three or four dose levels, a vehicle and a positive control were used. Groups consisted of 24 animals/sex/group. They were dosed on the basis of their average bodyweight, on days 8 and 15 of age, using dose volumes of up to 100 and 200 μl, respectively. Dose levels were selected on the basis of the results obtained in dose range finding studies, in which the MTD or the MFD (Maximum Feasible Dose) for neonatal mice, were determined. The pups were weaned around 22 days of age, housed 4/sex/cage and then maintained until 1 year of age, when they were sacrificed. DEN (diethylnitrosamine) at a dosage of 2 mg/kg dissolved in water was used as the positive control. (vHaras) Transgenic Mouse 8–9 weeks old Groups of 15 mice/sex/dose were randomly assigned to the study groups. The vehicles used for drugs and positive control agents were acetone, ethanol or DMSO. TPA (12otetradecanoylphorbol13acetate) was the positive control pound 26 weeks Hemizygous p53 +/– Knockout Mouse 6 to 10 weeks old, Genotype analysis was remended prior to assignment to dose groups Groups of 15 mice/sex/group, Three dose levels, a vehicle and a positive control were used. Two additional groups of 15 wildtype mice/sex/group received the vehicle and the high dosage of the test pound. pCresidine at 400 mg/kg/day by gavage in corn oil (10ml/kg), or benzene at 100 mg/kg/day by gavage in corn oil (5 ml/kg) were remended as positive controls. 18 to 24 month bioassay carcinoGENOMICS Development of a high throughput genomicsbased test for assessing genotoxic and carcinogenic properties of che
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