tretinoin and ethylphenylpropiolate

Topics: Alkynes; Animals; Cell Differentiation; Cytoplasmic Granules; Epidermis; Hair; Hyperplasia; Keratins; Phorbol Esters; Phorbols; Protein Biosynthesis; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

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.

Topics: Alkynes; Animals; Carcinogens; Diterpenes; DNA; Female; Mice; Mice, Hairless; Skin; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin

More than one application of the potent tumor-promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA), to mouse skin at intervals of more than 48 h led to a larger induction of ornithine decarboxylase (EC 4.1.1.17; ODC) than did a single application. In contrast, at intervals of less than 24 h, the first application of TPA appeared to induce a refractory state; the second application of TPA did not induce ODC. The extent of the inhibitory effect caused by the first application of TPA was dependent on the dose. The abilities of a series of phorbol esters to induce the refractory state correlated with their promoting abilities. However, both mezerein and ethylphenylpropiolate, potent hyperplastic agents with little or no promoting properties, induced the refractory state. On the other hand, pretreatment with TPA caused a refractory effect on ODC induction by mezerein but potentiated ODC induction by ethylphenylpropiolate. The epidermal cells escaped from the refractory state by repeated application of TPA at intervals of 24 h as well as at intervals of twice a week; that is, there was a full induction of ODC activity following a second application within 24 h of a prior application. TPA did not elicit production of detectable ODC-antizyme activity in mouse epidermis. Mixing of a soluble extract from mouse epidermis in the refractory state with that from TPA-stimulated epidermis gave essentially additive ODC activity. Elimination of ODC induction by topical application of retinoic acid or injection of cycloheximide concurrent with the first application of TPA did not restore the ability of a second application of TPA to induce ODC. These results suggest that the refractory effect on ODC induction by TPA does not result from feedback regulation of ODC.

Topics: Acetone; Alkynes; Animals; Carcinogens; Cycloheximide; Diterpenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Induction; Epidermis; Female; Mice; Ornithine Decarboxylase; Papilloma; Phorbols; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin