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Failure of the Phorbol Ester 12-O-Tetradecanoylphorbol-13-acetate to Enhance Sister Chromatid Exchange, Mitotic Segregation, or Expression of Mutations in Chinese Hamster Cells¹

Biomedical Sciences Division, L-452, Lawrence Livermore Laboratory, Livermore, California 94550 [L. H. T., A. V. C., K. W. B.], and Department of Biology and Center for Cancer Research, E17-220, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [R. M. B.]

The potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was tested for its ability (a) to induce sister chromatid exchange, (b) to increase the rate of transition at the adenine phosphoribosyltransferase (aprt) locus from the presumptive heterozygous state (+/-) to the homozygous state (-/- or -), and (c) to enhance the frequency of mutations expressed after ultraviolet radiation mutagenesis. We have found no significant effect of TPA in any of these experiments. Sister chromatid exchange frequencies in both V79 and Chinese hamster ovary cells remained unchanged by TPA treatment under various conditions, a result inconsistent with the hypothesis that an important effect of TPA might be to increase the rate of chromosomal mitotic recombination (and hence segregation of recessive mutations) in a manner akin to increased chromatid recombination. We have also been unable to obtain evidence for mitotic recombination affecting the aprt locus in Chinese hamster ovary cells for which the rate of change to a high level of resistance to azaadenine was measured. The rate of 8.6 x 10^-7 mutation (and/or segregations) per cell generation assessed by fluctuation analysis was not increased by the continuous presence of TPA, 4 µg/ml, in the medium. In the third set of experiments, mutant frequencies in Chinese hamster ovary cells after ultraviolet mutagenesis were measured for the markers ouabain resistance, thioguanine resistance, and azaadenine resistance, under conditions with and without pretreatment with TPA before mutant selection. No convincing enhancement in mutation expression was observed. In summary, these results argue that promotion by TPA does not proceed by a mechanism involving genetic recombination or the altered expression of newly mutated alleles.

¹ This work was performed under the auspices of the United States Department of Energy by the Lawrence Livermore Laboratory under contract W-7405-ENG-48, and under Grants GM21665 (to R. M. B.) and CA14051 (to S. E. Luria) from NIH.

² To whom requests for reprints should be addressed, at: Biomedical Sciences Division, L-452, Lawrence Livermore Laboratory, P. O. Box 5507, Livermore, Calif. 94550.

Received 11/13/79. Accepted 5/21/80.

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