Effects of retinoic acid on epidermal DNA synthesis induced by 12-O-tetradecanoylphorbol-13-acetate, mezerein or ethylphenylpropiolate in hairless mice.

We examined the effects of retinoic acid (RA) on epidermal DNA synthesis, induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a strong tumor promoter; mezerein (MEZ), a strong second stage promoter or ethylphenylpropiolate (EPP), a weak tumor promoter. RA reduced the initial wave of epidermal DNA synthesis in a dose-dependent manner after a single application of TPA, MEZ or EPP. Doses of RA that maximally depressed epidermal DNA synthesis after single applications had an unexpected stimulatory effect when given as five applications over a period of 2 weeks. This might be due to synergistic actions of RA, since RA per se was mitogenic after repeated applications. However, the non-stimulatory 17 nmol dose of RA potentiated DNA synthesis in MEZ-treated epidermis to the same degree as the stimulatory 170 nmol dose did in TPA-treated epidermis. We therefore suggested that the potentiation of DNA synthesis seen in the long-term study could be mainly due to compensatory growth as a response to initial inhibition. Some observations distinguished the actions of RA in TPA- or MEZ-treated epidermis on the one hand from those in EPP-treated epidermis on the other: the dose of RA needed for inhibition was much larger in EPP-treated epidermis; the combination of RA and EPP was toxic, as observed in the long-term study; further reduction of the specific activity of DNA/labeling index (SA/LI) ratio was only demonstrated in TPA- or MEZ-treated epidermis. Compared with controls the epidermal SA/LI ratio was depressed after TPA, MEZ or EPP, indicating that the increased number of basal cells with DNA synthesis (LI) displayed a depressed rate of DNA synthesis.