Acetic acid, a potent stimulator of mouse epidermal macromolecular synthesis and hyperplasia but with weak tumor promoting ability

The effects of a single application of various dose levels of acetic acid or the weak tumor promoter, phorbol 12,13 ditetradecanoate, on the incorporation of thymidine ³H, cytidine ³H, and leucine ³H, into DNA, RNA, and protein of mouse epidermis, respectively, were determined and compared with histologic changes in the skin. Treatment with either 500 or 833 μmoles acetic acid induced a sequential and sustained stimulation of RNA, protein, and DNA synthesis, which was followed by extensive epidermal hyperplasia similar to that reported for the strong promoter and irritant, 12 O tetradecanoyl phorbol 13 acetate. A dose response relationship between the amount of acetic acid and the rate of DNA synthesis was found between the dose levels of 33 to 833 μmoles of acetic acid per application. The latter dose induced the maximum activation of thymidine ³H into DNA at 723% of control at 2 days, whereas 33 μmoles stimulated DNA synthesis earlier and peaked at 210% of control at 3 hr. Phorbol 12,13 ditetradecanoate also stimulated macromolecular synthesis in a similar sequence, though to a lesser degree. No observable inflammation and only a slight hyperplastic response were noted with phorbol 12,13 ditetradecanoate. Weekly applications of 667 μmoles of acetic acid produced a maximal tumor response of 0.73 papilloma/mouse after 32 wk of promotion. However, a weekly dose of 677 μmoles of acetic acid was essentially inactive when given in 2 divided doses. When croton oil was administered twice weekly at a 0.25% dose level, 10.2 papillomas/mouse were induced after 32 wk of promotion. The results showed that the previously considered nonpromoting inflammatory agent, acetic acid, must be a weak promoter. However, there was no correlation between stimulated macromolecular synthesis or hyperplasia and tumor promotion when phorbol esters were compared with acetic acid.