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Dose and Frequency Effect in Mouse Skin Tumor Promotion

Institute de Recherche Scientifique sur le Cancer, Villejuif, France [I. C., C. L., R. L.]; Institute of Epidemiology and Biometry, German Cancer Research Center, Heidelberg, Federal Republic of Germany [J. W., H. B.]; MRC Biostatistics Unit, Cambridge, United Kingdom [N. E. D.]; and International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France [H. Y.]

In order to study the influence of both dose and application frequency of tumor-promoting agents on tumor development, we conducted a largescale mouse skin two-stage carcinogenesis experiment. The back skins of 1110 CD-1 mice were painted once with 50 µg benzo(a)pyrene. These mice were divided into 24 groups according to subsequent schedules of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Mice were treated with TPA at five different frequencies, i.e., daily, or every second, 4th, 8th, or 16th day, and six different TPA doses per application were used (0.1, 0.2, 0.4, 0.8, 1.6, or 3.2 µg), which allowed groups to be established with the same total dose of TPA applied per time unit. Six of the 30 frequency/dose combinations at extreme low or high frequency and dose were excluded. At each fixed frequency of TPA application, there was a good dose-response of TPA in mouse skin papilloma incidence. There was also a good application frequency-response relationship at fixed doses of TPA application.

Within the set of groups in which animals received the same total dose of TPA per time unit, some variation was observed with respect to frequency of application. In general, TPA applications every 4th and 8th day tended to yield a small number of tumors.

¹ To whom requests for reprints should be addressed.

Received 3/22/88. Revised 9/13/88. Revised 12/ 5/88. Accepted 1/ 4/89.

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