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The Effect of the Phorbol Ester Tumor Promoters on the Basal and Catecholamine-stimulated Levels of Cyclic Adenosine 3':5'-Monophosphate in Mouse Skin and Epidermis in Vivo¹

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

To measure the in vivo levels of cyclic adenosine 3':5'-monophosphate (cyclic AMP) in mouse skin, precautions must be taken to avoid artifactual alterations after excision of the skin from the mouse. With such precautions, the level of cyclic AMP in mouse epidermal-dermal preparations was unchanged 1 to 18 hr after application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin. The accumulation of cyclic AMP in response to isoproterenol or the naturally occurring catecholamine epinephrine was, however, significantly diminished 9 to 24 hr after application of TPA. No enhanced accumulation of cyclic AMP in response to -adrenergic stimulation accompanied this diminished ß-adrenergic responsiveness. Experiments with pure epidermis confirmed that these observations reflected the effects of TPA on the epidermal cells in the epidermaldermal preparations. The metabolism of isoproterenol in TPA-treated epidermis was the same as that in control epidermis.

Finally, the tumor-promoting activity of various doses of TPA and of other phorbol esters correlated with their ability to diminish the ß-adrenergic responsiveness of the epidermis.

¹ This work was supported by Grants CA-07175, T32-CA09020, and CA-5002 from the National Cancer Institute.

² Recipient of National Cancer Institute Post Doctoral Fellowship F22 CA 00586-01.

Received 7/26/76. Accepted 12/ 6/76.