This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Raick, A. N. Articles by Chivers, B. R. Search for Related Content PubMed PubMed Citation Articles by Raick, A. N. Articles by Chivers, B. R.

Early Effects of 12-O-Tetradecanoyl-phorbol-13-acetate on the Incorporation of Tritiated Precursor into DNA and the Thickness of the Interfollicular Epidermis, and Their Relation to Tumor Promotion in Mouse Skin¹

Department of Pathology, University of Toronto, 100 College Street, Toronto, 2, Ontario, Canada

The macroscopic and histological changes induced in mouse skin by various doses of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were studied; its tumorigenic and tumorpromoting activity were tested, and the changes induced in the thickness of interfollicular epidermis (IFE) and in the rate of incorporation of thymidine-methyl-³H into skin DNA were measured. TPA in the dose range of 0.016 to 0.0016 mole shows marked promoting activity, while 0.00016 mole does not, thus suggesting a threshold for promoting activity between 0.0016 and 0.00016 mole. Doses of 0.08 and 0.16 mole of TPA induce marked necrosis and ulceration of the skin and are therefore unsuitable for studies of tumor-promoting activity. The changes in the rate of incorporation of thymidine-methyl-³H into DNA and the thickness of IFE are dose dependent in degree and duration. A single application of TPA induces initially an inhibition in the incorporation of thymidine-methyl-³H into DNA, followed by marked stimulation in the rate of incorporation and returning to control levels thereafter. Following a second application of TPA, 168 hr after the first, the initial inhibition of thymidine-methyl-³H incorporation into DNA is not observed, and the onset of the increase in the rate of incorporation is earlier and its peak is higher. A single application of TPA induces a marked increase in the thickness of IFE, but this reverts to the control level between 120 and 168 hr later. After a second application, the increase in the thickness of IFE is 1.5 to 2.0 times higher, and the peak of thickness is reached earlier than after a single application, suggesting that the first application of TPA potentiates the effects of subsequent applications. There is a correlation between the increase in thickness of IFE and skin tumor promotion with 0.016 and 0.0016 mole of TPA. However, 0.00016 mole of TPA induces a significant increase in the thickness of IFE and in the rate of incorporation of thymidine-methyl-³H into DNA but does not show promoting activity, indicating that the threshold for epidermal hyperplasia is different from that for promoting activity and suggesting that hyperplastic action and promoting action are independent phenomena.

¹ This work was supported by Grant-in-Aid 4201 from the National Cancer Institute of Canada, and by Medical Research Council of Canada Grant MA-4340.

² To whom requests for reprints should be addressed.

Received 1/20/72. Accepted 4/10/72.