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Effect of Phorbol Myristate Acetate on the Recovery of Spontaneous and Ultraviolet Light-induced 6-Thioguanine and Ouabain-resistant Chinese Hamster Cells¹

Department of Human Development, Michigan State University, East Lansing, Michigan 48824 [J. E. T., C. C. C., L. P. Y.], and Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109

12-O-Tetradecanoyl-phorbol-13-acetate (TPA) and phorbol were tested in Chinese hamster cells for their effects on mutagenesis (resistance to 6-thioguanine and to ouabain), DNA repair, and survival after ultraviolet (UV) irradiation. Recovery of 6-thioguanine- and ouabain-resistant colonies was significantly increased by TPA treatment and, to a lesser extent, by phorbol in UV-irradiated cells. Moreover, maximum enhancement of recoverable UV-induced 6-thioguanine- and ouabain-resistant mutants occurred when TPA was present after the mutation "expression" time and after the completion of DNA repair. This enhancement effect, while persisting up to 18 days in the 6-thioguanine mutation system, was maximal when TPA was applied about 2 days after UV irradiation for the ouabain resistance mutation system. No significant decrease in cell survival was noted after post-UV treatment with TPA or phorbol, under conditions where there was a slight but nonspecific inhibition of unscheduled DNA repair synthesis. These results do not support the hypothesis that the tumor-promoting activity of TPA is due to its ability to inhibit "error-free" excision repair. The results are, however, consistent with a "two-stage" hypothesis of carcinogenesis which includes mutational and epigenetic mechanisms to explain the initiation and promotion phases.

¹ This work was supported by Grants CA13048-04 and CA24085-05 from the National Cancer Institute.

² Recipient of a National Cancer Institute Research Career Development Award. To whom requests for reprints should be addressed.

Received 8/15/75. Accepted 10/13/76.

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