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Effects of 3-Isobutyl-1-methylxanthine and Cyclic Nucleotides on 12-O-Tetradecanoylphorbol-13-acetate-induced Ornithine Decarboxylase Activity in Mouse Epidermis in Vivo¹

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

A single topical application of 8.5 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin induced rapid and transient increases in the levels of both guanosine cyclic 3':5'-monophosphate and adenosine cyclic 3':5'-monophosphate, followed by the stimulation of ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activity. Peak syntheses of guanosine cyclic 3':5'-monophosphate and adenosine cyclic 3':5'-monophosphate were achieved within 10 and 60 min, respectively, while ODC activity was maximally stimulated between 4.5 and 6 hr. The increased levels were dose dependent and correlated with the tumor-promoting abilities of diverse compounds. However, the magnitudes of the cyclic nucleotide and ODC responses to TPA were quite different (3- to 7- and 70-fold, respectively).

A single topical application of 10 µmol of 3-isobutyl-1-methylxanthine (IBMX), which was able to raise the levels of cyclic nucleotides almost as much as did TPA, produced only a 9-fold increase in ODC activity. IBMX, as well as other phosphodiesterase inhibitors, enhanced the magnitude and the duration of the increases in cyclic nucleotide levels and ODC activity produced by TPA. Maximum stimulation of TPA-induced ODC activity was achieved when IBMX was applied within the 30-min time interval preceding TPA treatment. As a result of the IBMX pretreatment, the same or higher levels of cyclic nucleotides and ODC activity could be induced with about 10 times less TPA or with weak and moderate tumor promoters, as compared with the increased levels attributable to TPA alone. However, in the presence of IBMX, a discrepancy was still observed between the magnitude of the increased cyclic nucleotide response to TPA (6- to 14-fold) and the 150-fold induction of ODC activity produced by TPA.

In addition, single or combined topical treatments with guanosine cyclic 3':5'-monophosphate and adenosine cyclic 3':5'-monophosphate were unable to mimic the effect of TPA on ODC activity and even depressed significantly basal and TPA-induced ODC activities in the presence of IBMX. Therefore, the findings presented in this and an accompanying paper suggest that, in mouse epidermis in vivo, if TPA-increased cyclic nucleotides participate in the molecular mechanism by which ODC activity is induced, their controlled degradation may be equally important.

¹ This material was presented in part at the Annual Meeting of the American Association for Cancer Research, San Diego, Calif., May 1980 (42). This investigation was sponsored by Grants CA-07175 and CA-22484 from the NIH. This is Paper 1 in a series exploring the role of cyclic nucleotides in the mechanism of action of TPA. Ref. 43 is the following paper in this series.

Received 3/18/81. Accepted 7/15/81.