DNA adducts, cell proliferation and papilloma latency time in mouse skin after repeated dermal application of DMBA and TPA.

Abstract

The mouse skin tumor model was used to investigate whether the level of DNA adducts and/or the rate of cell division in the epidermis are indicators of the risk of cancer formation for an individual in an outbred animal population. A high risk was considered to be reflected by a short latency period for the appearance of a papilloma. Female NMRI mice were treated twice weekly with 2.5 nmol 7,12-dimethylbenz[a]anthracene (DMBA) and 3 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) and the appearance of papillomas was registered. The first papilloma appeared after 7.5 weeks. After 17 weeks, when 12 of 14 mice had at least one papilloma, an osmotic minipump delivering 5-bromo-2'-deoxyuridine (BrdU) was implanted into each mouse for 24 h. The mice were killed after 24 h and the epidermis was analyzed for DMBA-nucleotide adducts by 32P-postlabeling, for the cell number per unit skin length, and for the labeling index for DNA synthesis. Unexpectedly, DMBA-nucleotide adduct levels were highest in those animals which showed the longest latency periods. Adduct levels were negatively correlated with the labeling index, indicating that dilution of adducts by cell division was a predominant factor in determining average adduct concentrations. Individual tumor-latency time was not correlated with either cell number or labeling index. This could be due to the fact that the measurements only provided averaged data and gave no information on the specific situation in clones of premalignant cells. Under the conditions of this assay, therefore, neither DNA adduct levels nor information on the average kinetics of cell division had a predictive value for the individual cancer risk within a group of outbred animals receiving the same treatment.