The Nature of the Epidermal Growth Produced by the First Application of 12-0-Tetradecanoyl-Phorbol-13-Acetate on the Skin of Mice Initiated with Dimethylbenzanthracene

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One of the important areas of investigation today concerning skin chemical carcinogenesis in mice is the nature of the epidermal growth produced by the application of a tumor promoter on initiated mouse skin. We have investigated the kinetics of epidermal growth following a single application of 17 nmoles of 12-0-tetradecanoyl-phorbol-13-acetate (TPA) in the back skin of CD-1 female mice initiated with 200 nmoles of dimethylbenzanthracene (DMBA). Within 5 hr after the application of TPA there is an increase in epidermal wet weight and total protein (protein/unit area of epidermis) which reached their peak of 3 to 4× that of normal between 3 and 4 days. Total DNA begins to significantly increase somewhat slower than epidermal wet weight and total protein, but reaches its peak of about 2× increase above normal by day 2. All these parameters remain elevated until 7 days after TPA treatment when they begin to return toward normal levels. But, by day 10, the end of the experimental period, they are still significantly elevated above normal levels. Within 3 hr after TPA application, a slight hyperplasia is seen, as evidenced by small increases in the number of nucleated cell layers, the total number of epidermal nuclei/mm interfollicular epidermis (IFE) and the number of suprabasal nuclei/mm IFE. This modest hyperplasia is transient and is lost by 8 hr. Then the principal hyperplasia appears with marked increases in the number of nucleated cell layers, the total number of nuclei/mm IFE and the number of suprabasal nuclei/mm IFE which by day 2 reach their peak of about 2-3× normal. During the transient hyperplasia and the early phase of the principal hyperplasia one sees considerable epidermal cell damage as evidenced by cytoplasmic vacuolization, nuclear pyknosis, and the separation of the epidermis from the dermis. This period of damage is associated with a decrease in the number of basal nuclei/mm IFE. A small increase in mitotic activity of the basal epidermal cells is seen at 3 hr at the time the transient hyperplasia occurs. Mitotic activity decreases to below normal levels by 5 hr, and then, as the principle hyperplasia begins to be produced, epidermal mitotic activity increases markedly, reaching a peak at day 1. A Comparison of the epidermal growth produced by the first application of TPA in initiated mouse skin with that in normal mouse skin, suggests that the overall growth produced by the first application of TPA in initiated mouse skin is of greater duration than that produced by TPA in normal mouse skin.