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Inhibition by Putrescine of the Induction of Epidermal Ornithine Decarboxylase Activity and Tumor Promotion Caused by 12-O-Tetradecanoylphorbol-13-acetate¹

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

The induction of epidermal ornithine decarboxylase (EC 4.1.1.17) (ODC) following topical application of the tumorpromoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) to mice can be inhibited by topical application of putrescine, the product of the enzyme. The degree of inhibition depended on both the dose and the time of putrescine application; application of 20 µmol of putrescine 2 hr after TPA treatment inhibited the induction of ODC activity by 50%. TPA-induced activity of another polyamine-biosynthetic enzyme, S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), was unaffected by application of putrescine. Among several amines tested for their ability to inhibit the induction of ODC activity, spermidine, 1,7-diaminoheptane, and spermine were the most effective, causing a 90% inhibition at the 20-µmol dose.

Putrescine, when added directly to the assay medium at a 100-µmol dose level inhibited by 97% the TPA-induced ODC activity, but the amount of putrescine (20 µmol) which gave 50% inhibition of the induction of ODC activity in vivo had no effect when added to the assay system. Mixing of soluble extracts from TPA-treated mouse epidermis posttreated either with acetone or putrescine or with mouse epidermis treated with putrescine alone gave essentially additive ODC activity. Furthermore, putrescine did not elicit production of detectable ODC-antizyme activity in mouse epidermis.

Putrescine inhibited the formation of mouse skin papillomas promoted with TPA. Topical application of 20 and 100 µmol of putrescine 2 hr after each application of TPA to mice initiated with 7,12-dimethylbenz[a]anthracene resulted in a 30 and 80% inhibition, respectively, of papilloma formation compared to animals receiving no putrescine.

¹ The work was supported by Grants CA-07175, CA-22484, and CA-09135 from the National Cancer Institute, USPHS.

² To whom requests for reprints should be addressed.

Received 4/10/80. Accepted 7/24/80.