Effect of retinoic acid pretreatment on 12-O-tetradecanoylphorbol-13-acetate-induced cell population kinetics and polyamine biosynthesis in hairless mouse epidermis

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Abstract
A single topical application of 17 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) to the skin of hairless mice induces characteristic transient alterations in the epidermal cell turnover and maturation (0-96 h), associated in time with characteristic changes in the activities of L-ornithine carboxy-lyase (EC 4.1.1.17) (ODC) and S-adenosyl-L-methionine carboxy-lyase (E.C. 4.1.1.50) (SAM-D) and in the accumulation of polyamines. The effects on these responses of local pretreatment of the skin with retinoic acid 1 h prior to TPA were investigated at selected time points. Retinoic acid inhibited the TPA-induced ODC activity and the ensuing accumulation of putrescine, but did not alter the TPA-induced SAM-D activity or the molar ratio of spermidine/spermine. This pretreatment also decreased the number of dividing basal cells in the first TPA-induced synchronized wave of proliferating cells. During the subsequent period of proliferation, the number of dividing cells in the retinoic acid pretreated group was comparatively increased. Hence, at 4 dose levels of retinoic acid (0.17, 1.70, 17.0 and 170 nmol), which all inhibited the TPA-induced ODC effectively, there was no change in the total number of basal cells that divided during 16-48 h after TPA-application. Retinoic acid might exert its antitumorigenic effect during tumor promotion with TPA by interfering with the rate and/or quality of epidermal cell maturation, rather than by inhibiting cell proliferation.