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Effects of Varying the Onset and Duration of Exposure to Phenobarbital on Its Enhancement of 2-Acetylaminofluorene-induced Hepatic Tumorigenesis¹

Division of Biological and Medical Research, Argonne National Laboratory, Argonne, Illinois 60439

In previous experiments we observed that the short-term feeding of 2-acetylaminofluorene (AAF) at a low dietary concentration resulted in the late appearance of well-differentiated hepatic tumors at low incidence levels. When the AAF treatment was followed by the feeding of a phenobarbital-supplemented diet, the appearance of these tumors was accelerated, and their overall incidence levels were increased. The present study examined the characteristics of this interaction between the effects of AAF and phenobarbital by measuring tumor production after changing either the duration of the interval between AAF and phenobarbital treatments or the duration of the post-AAF exposure to phenobarbital.

When AAF and phenobarbital treatments were separated by increasing intervals (up to 120 days), the resultant levels of tumor enhancement appeared to be influenced mainly by the duration of the post-AAF phenobarbital treatment rather than by the length of the treatment-free inteval. Progressive increases in the duration of the phenobarbital treatment (begun within 7 days after the AAF treatment) advanced the time at which tumor enhancement occurred and similarly increased overall tumor incidence levels. The latter enhancement effects occurred and were sustained after the cessation of the phenobarbital treatments. The results of this study suggest that (a) the tumorigenic changes induced by brief AAF treatment are persistent, although the question of their permanence remains open, and (b) phenobarbital treatment produces irreversible changes in AAF-modified cells, which lead to the expression of the tumor phenotype.

¹ This work was supported by the United States Energy Research and Development Administration.

Received 1/13/77. Accepted 6/30/77.