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Similar, Potent Tumor-promoting Activity of All Isomers of Teleocidins A and B in a Two-Stage Carcinogenesis Experiment on the Skin of CD-1 Mice¹

National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Tokyo 104 [H. F., M. S., M. N., S. Y., K. Y., S. T.]; Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Chiba 260 [Y. H., S. S.]; Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113 [K. S.]; and National Cancer Center, 1-1, Tsukiji 5-chome, Tokyo 104 [T. S.], Japan

Teleocidin, isolated from mycelia of Streptomyces mediocidicus is a mixture of two teleocidin A isomers with molecular weights of 437 (A-1 and A-2) and four teleocidin B isomers with molecular weights of 451 (B-1, B-2, B-3, and B-4). Previously we found that each purified isomer of teleocidins A and B had approximately the same activity as teleocidin in an irritant test on mouse ear, in inductions of ornithine decarboxylase in mouse skin and adhesion of human promyelocytic leukemia (HL-60) cells, and in inhibition of the specific binding of [³H]-12-O-tetradecanoylphorbol-13-acetate to a mouse skin particulate fraction. This paper reports the strong activation of protein kinase C in vitro by each isomer of teleocidins A and B at a concentration of 1 µg/ml. Detailed studies on the potent tumor promoting activities of the two teleocidin A isomers and four teleocidin B isomers in a two-stage carcinogenesis experiment on mouse skin are also reported, including histological findings on the tumors. Treatment of mice with 100 µg of 7,12-dimethylbenz(a)anthracene and then 2.5 µg of any one of the six isomers of teleocidins A and B twice a week induced tumors in 80.0 to 91.7% of the mice with 2.8 to 5.2 tumors/mouse in week 30. Scarcely any tumors developed in groups treated with 7,12-dimethylbenz(a)anthracene or any one of the isomers of teleocidins A or B alone. The percentages of incidences of mice bearing papillomas and carcinomas in the six groups treated with 7,12-dimethylbenz(a)anthracene plus one isomer of teleocidins A or B were 90.9 to 98.3% and 1.7 to 9.1%, respectively. These results indicate that all of the isomers of teleocidins A and B have potent tumor promoting activity on mouse skin, irrespective of the structural differences between teleocidins A-1 and A-2, and among the four isomers of teleocidin B.

The structure-activity relationship of teleocidins A and B is discussed on the basis of our recent results. Based on the structures of related compounds, we propose a revised numbering system for compounds of the teleocidin class.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture and the Ministry of Health and Welfare, for a Comprehensive 10-Year Strategy for Cancer Control, Japan and by grants from the Foundation for Promotion of Cancer Research and the Princess Takamatsu Cancer Research Fund. M. Ninomiya and K. Yamishita thank the Foundation for Promotion of Cancer Research, Japan for support in work at the National Cancer Center Research Institute, Tokyo.

² To whom requests for reprints should be addressed.

Received 8/31/87. Revised 3/ 8/88. Accepted 4/28/88.