Suppression of the first stage of phorbol 12-tetradecanoate 13-acetate-effected tumor promotion in mouse skin by nontoxic inhibition of DNA synthesis.

Abstract

To evaluate the significance of epidermal cell proliferation for the 1st stage of skin tumor promotion, the effect of hydroxyurea (HU), an inhibitor of DNA synthesis, on tumor formation was studied. Mice initiated with 7,12-dimethylbenz[a]anthracene received a single dose of phorbol 12-myristate 13-acetate (PMA) in stage I of promotion, followed by twice weekly application of the irritant skin mitogen phorbol 12-retinoate 13-acetate in stage II. A single dose of HU given i.p. at different times before or after treatment with PMA interfered with tumor formation, exhibiting an almost complete inhibition if administered 18 h after PMA.sbd.i.e., at the time of maximal DNA synthesis. The inhibition of tumor formation by HU in the 2-stage promotion experiment did not prevent a subsequent promotion of cells by repetitive PMA treatment. The inhibitory effect of HU was due neither to cytotoxicity (killing of initiated cells) nor to an interference with initiation. Epidermal DNA synthesis apparently is obligatory for PMA-induced 1st-stage promotion. The causal relationship between both events remains to be established.