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Differential Effects of Retinoic Acid and 7,8-Benzoflavone on the Induction of Mouse Skin Tumors by the Complete Carcinogenesis Process and by the Initiation-Promotion Regimen¹

Division of Clinical Oncology, Department of Human Oncology, Wisconsin Clinical Cancer Center [A. K. V.], and McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706 [E. A. C., R. K. B.]

The present study was designed to elucidate differences in the mechanism of the induction of mouse skin tumors either by the initiation-promotion regimen or by the complete carcinogenesis process. The protocols used to elicit skin tumors were: (a) by the initiation-promotion regimen, a single application of 0.2 µmol of 7,12-dimethylbenz[a]anthracene (DMBA) followed by twice-weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA); and (b) by the complete carcinogenesis process, a single application of 3.2 µmol of DMBA without TPA treatment, or 0.2 µmol of DMBA applied once weekly, or 1, 10, 50, or 100 nmol of DMBA applied twice weekly without application of TPA. The biology of tumor formation by the initiation of tumors with a single application of 0.2 µmol of DMBA followed by twice-weekly applications of TPA differs from tumor induction by once-weekly 0.2-µmol doses of DMBA. In the latter case, papillomas developed more slowly and were less common (the tumor induction time was long; tumor yield was less), but carcinomas appeared much earlier. Retinoic acid, a potent inhibitor of tumor promotion by TPA, failed to inhibit and under some experimental conditions significantly (p < 0.001) enhanced tumor formation by DMBA. Also, retinoic acid did not inhibit ornithine decarboxylase induction by DMBA. In contrast, 7,8-benzoflavone, which did not inhibit the induction of ornithine decarboxylase activity by TPA, inhibited the induction of ornithine decarboxylase activity and tumor formation by DMBA.

The results indicate that the nature and the mechanism of the biochemical events elicited by the presumed promoting component of carcinogenesis by a complete carcinogen are different from those of the tumor promoter TPA.

¹ This work was supported by Grants CA-07175 and CA-22484 from NIH.

² To whom requests for reprints should be addressed, at the Department of Human Oncology, Wisconsin Clinical Cancer Center, University of Wisconsin Center for Health Sciences K4/538, 600 Highland Avenue, Madison, Wis. 53792.

Received 12/10/81. Accepted 5/28/82.

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