Targeted antizyme expression in the skin of transgenic mice reduces tumor promoter induction of ornithine decarboxylase and decreases sensitivity to chemical carcinogenesis

To directly evaluate the role of increased ornithine decarboxylase (ODC) an d polyamines in mouse skin carcinogenesis, we used bovine keratin 5 (K5) an d keratin 6 (K6) promoter elements to direct the expression of antizyme (AZ ) to specific skin cell populations. AZ is a multifunctional regulator of p olyamine metabolism that inhibits ODC activity, stimulates ODC degradation, and suppresses polyamine uptake. K5-AZ mice treated with 12-O-tetradecanoy lphorbol-13-acetate (TPA) at 0 and 24 h exhibit increases in epidermal and dermal ODC activity that are reduced in magnitude. K6-AZ mice treated simil arly do not show any increased ODC activity or protein after a second appli cation due to TPA-induced expression of AZ protein. Epidermal and dermal po lyamine content, particularly spermidine, is reduced in untreated KS-AZ mic e and TPA-treated K5-AZ and K6-AZ mice. Susceptibility to 7,12-dimethylbenz (a)anthracene/TPA carcinogenesis was also investigated for two K6-AZ transg enic lines [K6-AZ(52) and K6-AZ(18)] and a single K5-AZ line. K6-AZ(52) mic e had a substantial delay in tumor onset and a > 80% reduction in tumor mul tiplicity compared with normal littermates. K6-AZ(18) and K5-AZ mice also d eveloped fewer papillomas than littermate controls (35% and 50%, respective ly), and the combination of these lines to produce double transgenic animal s yielded an additive decrease (70%) in tumor multiplicity. These mice demo nstrate for the first time that suppresses tumor growth in an animal cancer model and provide a valuable model system to evaluate the role of ODC and polyamines in skin tumorigenesis.