Effects of varying the exposure to phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat.

In a previous study, phenobarbital feeding enhanced hepatic tumorigenesis in rats previously fed 2-acetylamino-fluorene (AAF). The present study analyzed this enhancement by comparing tumor incidences in rats fed phenobarbital for various periods following a fixed exposure to AAF. A 5- or 20-day treatment with phenobarbital immediately after cessation of AAF feeding produced little tumorigenic enhancement, in comparison with the severalfold enhancement seen in rats receiving phenobarbital for 100 days and longer. On the other hand, the interposition of a 10- or 30-day interval between the cessation of AAF treatment and the beginning of phenobarbital treatment (which was then continued throughout the experiment) produced exhancement comparable to that produced by beginning the phenobarbital treatment immediately after cessation of AAF feeding. These results indicated that ( a ) prolonged exposure to phenobarbital was required for tumorigenic enhancement and ( b ) the tumorigenic lesion produced by AAF was relatively stable, and its expression could be enhanced by phenobarbital long after the cessation of AAF treatment. Observation of the kinetics of tumor incidence throughout the experiment showed that phenobarbital: ( a ) decreased the latent period between the end of the carcinogen treatment and the appearance of tumors; ( b ) increased the growth rate of the tumors; and ( c ) increased the rate of appearance of new tumor foci. No metastases were seen in rats given AAF alone or followed by phenobarbital, and the morphological characteristics of the tumors were similar with both types of treatment. Phenobarbital, therefore, did not appear to alter the degree of differentiation of the tumors.