Interaction of phorbol derivatives with replicating cells.

The significance of the interaction of phorbol derivatives with replicating cells has been studied in HeLa cells and in tumour promotion experiments. Dose-response relationships for the radiomimetic activity of phorbol derivatives in HeLa cells (Kinzel et al., 1980) were obtained by analysis of the degree of transient blockage in G2 phase of the cell cycle. HeLa cells are shown to be one order of magnitude more sensitive to 12-O-tetradecanoylphorbol-13-acetate (TPA) than to equally mitogenic and irritant but much less promoting derivatives. The susceptibility of HeLa cells reflects the promoting capacity of these compounds. Studies on effects of modifiers on TPA-induced G2 blockage indicate that the influence of TPA, even in a single cell cycle phase, may be the result of a 'multiple site' attack. The significance of the interaction of TPA with replicating mouse epidermal cells in tumour promotion has been demonstrated in animal experiments after initiation with 7-12-dimethylbenz[a]anthracene by using a two-stage protocol which effects promotion with a single dose of TPA followed by repeated treatment with 12-O-retinoylphorbol-13-acetate (Fürstenberger et al., 1981). A single dose of the inhibitor of DNA synthesis, hydroxyurea, given to groups of mice at different times before and after treatment with TPA interferes with tumour formation; almost complete inhibition is observed after 18 h. The interaction of TPA and DNA-synthesizing cells seems to be of crucial importance to the first stage of tumour promotion.