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Paradoxical Effect of Anthralin on 12-O-Tetradecanoylphorbol-13-acetate-induced Mouse Epidermal Ornithine Decarboxylase Activity, Proliferation, and Tumor Promotion

Syntex Research, Palo Alto, California 94304, and SRI International, Menlo Park, California 94025

Anthralin, a weak promoter of mouse skin tumorigenesis, actually inhibits tumorigenesis when applied either before each promoting application of the potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), or twice in the interval between initiation with 200 nmol 7,12-dimethylbenz(a)anthracene and the beginning of promotion with TPA (8.5 nmol for all tumor experiments).

In tumor experiments, when 8.8 nmol anthralin were applied 2 hr prior to each twice-weekly promoting dose of TPA, the number of tumors per mouse was reduced by 20%; with 88 nmol anthralin, the number of tumors per mouse was reduced by 40 to 60%. If two applications of 88 nmol anthralin were given 2 hr prior to the first two promoting applications of TPA only, tumorigenesis was inhibited by 30%. However, if 88 nmol anthralin were applied once 1 week after initiation and once 1 week later and TPA promotion was begun 48 hr after the second dose, tumorigenesis was inhibited by 70%.

In biochemical determinations, a single pretreatment with either dose of anthralin inhibited ornithine decarboxylase (ODC) activity induced by a single application of TPA by about 75% and [³H]thymidine incorporation into DNA by 20 and 60% for the 8.8-nmol and 88-nmol dose, respectively. After four repetitions of the anthralin plus TPA treatment at 2- to 3-day intervals, the 8.8-nmol anthralin pretreatment was without inhibitory effect on either ODC activity or DNA synthesis, while 88 nmol anthralin inhibited both activities by about 40%.

Histologically, at either dose of anthralin, a single anthralin plus TPA treatment resulted in considerable epidermal destruction. Treatment with any of the chemicals alone did not cause such destruction, nor was destruction evident for either dose of anthralin after the fourth anthralin plus TPA treatment. Moreover, the skin of animals given anthralin between initiation and the first application of TPA did not show epidermal destruction.

Since the animals in the previous experiment did not show epidermal destruction and since anthralin loses its ability to inhibit TPA-induced ODC activity when applied more than 24 hr before TPA, neither a generalized epidermal cytotoxicity nor an inhibition of TPA-induced ODC activity appears to totally explain the mechanism of anthralin-mediated inhibition of tumorigenesis. We have therefore suggested that immunological mechanisms may be a factor in our results.

¹ To whom requests for reprints should be addressed.

Received 4/16/80. Accepted 10/ 6/80.