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Radiomimetic Activity of Phorbol Esters Exerted in HeLa Cells in Comparison with Their Tumor-promoting Capacity¹

German Cancer Research Center, Institutes of Experimental Pathology [V. K., J. R.] and of Biochemistry [F. M., G. F.], Im Neuenheimer Feld 280, D-6900 Heidelberg, Federal Republic of Germany

The biological activities exerted in mouse skin by three closely related phorbol esters were compared with the effects of these compounds on HeLa cells. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate has been shown previously to influence various cell cycle parameters of these cells, thereby mimicking X-irradiation [Kinzel, V., Richards, J., and Stöhr, M. Science (Wash. D. C.), 210: 429–431, 1980]. Qualitatively similar effects were exerted by the mitogenic and irritant but almost nonpromoting "incomplete" phorbol esters 12-O-tetradeca-2-cis-4-trans-6,8-tetraenoylphorbol-13-acetate and 12-O-retinoylphorbol-13-acetate. Cell cycle parameters were analyzed by measuring thymidine incorporation rates, labeling indices, DNA histograms gained through flow cytometry, and mitotic activity. In every case, 12-O-tetradecanoylphorbol-13-acetate was more effective than 12-O-tetradeca-2-cis-4-trans-6,8-tetraenoylphorbol-13-acetate or 12-O-retinoylphorbol-13-acetate. The analysis of the influence of phorbol esters in G₂ phase showed that, in order to reach the effectiveness of 10^-8 M 12-O-tetradecanoylphorbol-13-acetate, approximately 10 times the concentration of either 12-O-tetradeca-2-cis-4-trans-6,8-tetraenoylphorbol-13-acetate or 12-O-retinoylphorbol-13-acetate has to be applied. Therefore, the susceptibility of replicating HeLa cells to these phorbol derivatives reflects the promoting rather than the mitogenic and irritant capacity of these compounds.

¹ Dedicated to Professor Dr. O. Westphal on the occasion of his 70th birthday.

This work was supported by the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed.

Received 8/25/82. Accepted 9/30/83.