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Absence of Synergistic Effects on Tumor Promotion in CD-1 Mouse Skin by Simultaneous Applications of Two Different Types of Tumor Promoters, Okadaic Acid and Teleocidin¹

Cancer Prevention Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan

Okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A, and teleocidin, an activator of protein kinase C, are both potent tumor promoters on mouse skin. The effects of simultaneous treatment of the two different types of tumor promoters on tumor promotion as well as on their biochemical activities were studied. Three independent experiments with different doses of tumor promoters revealed that simultaneous repeated applications of okadaic acid and teleocidin did not induce any synergistic or additive effects on tumor promotion in mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA). In Experiment 1, the group treated with a single application of DMBA, followed by repeated applications of 1.0 µg (1.2 nmol) okadaic acid and 2.5 µg (5.7 nmol) teleocidin, resulted in 64.3% tumor-bearing mice at week 20. But the groups treated with DMBA plus okadaic acid or DMBA plus teleocidin gave 73.3% and 71.4%, respectively. The biochemical activities were studied by means of induction of ornithine decarboxylase in mouse skin and protein phosphorylation in the cells. Simultaneous application of okadaic acid at three different doses with teleocidin did not induce ornithine decarboxylase activity synergistically or additively. Phosphorylation of proteins, cytokeratins, or heat shock protein 27 was not synergistically increased in human keratinocytes treated with okadaic acid and teleocidin, although the cotreatment in a cell-free system synergistically increased protein phosphorylation. Thus, the absence of synergistic effects on tumor promotion in mouse skin was also confirmed in two systems, induction of ornithine decarboxylase in mouse skin and protein phosphorylation in human keratinocytes. The effect of cotreatment of okadaic acid and teleocidin is discussed at the molecular level.

¹ Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture and from the Ministry of Health and Welfare; a grant from a Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan; and grants from the Foundation for Promotion of Cancer Research, the Uehara Memorial Life Science Foundation, the Princess Takamatsu Cancer Research Fund, and the Smoking Research Foundation of Japan.

² To whom requests for reprints should be addressed.

Received 8/10/92. Accepted 12/22/92.