Previous studies have shown that
keratin 6 (K6)-
spermidine/
spermine N1-acetyltransferase (SSAT) transgenic mice, which modestly over-express SSAT in the skin, are more sensitive to
tumor induction by a two-stage
tumorigenesis protocol using initiation with 7,12-dimethylbenz[a]
anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). To evaluate the role of altered levels of
polyamines and oxidative stress in this increase, studies were carried out with pharmacologic and genetic manipulation of K6-SSAT mice subjected to DMBA/TPA
carcinogenesis. The increased
tumor incidence was partially prevented by treatment with 1,4-bis-[N-(buta-2,3-dienyl)amino]
butane, an inhibitor of acetylpolyamine
oxidase which prevented degradation of the acetylated
polyamines. This result suggests that toxic products such as
reactive oxygen species and
aldehydes liberated by the action of
polyamine oxidase on the acetylated
polyamines formed by SSAT may enhance
tumor development. Breeding of the K6-SSAT mice with K6-antizyme (AZ) mice [which express AZ, a negative regulator of
ornithine decarboxylase (ODC)] blocked the development of
tumors. In addition, treatment of
tumor-bearing K6-SSAT mice with the ODC inhibitor,
alpha-difluoromethylornithine, resulted in the complete regression of established
tumors. In contrast, treatment with N1,N11-bis(ethyl)norspermidine which increased SSAT activity in the
tumors did not enhance regression. These results indicate that the
tumor progression in K6-SSAT mice is dependent on elevated ODC activity and increased
putrescine levels and may be further enhanced by oxidative stress. They support the use of strategies to modulate
polyamine levels through the inhibition of ODC activity or
polyamine uptake, but not via increased SSAT expression, for
cancer chemoprevention in individuals at high risk for skin
tumor development.