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Effects of Varying the Dietary Concentration of Phenobarbital on Its Enhancement of 2-Acetylaminofluorene-induced Hepatic Tumorigenesis¹

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

Studies in this laboratory first showed that the incidence of hepatic tumors induced by a brief exposure to dietary 2-acetylaminofluorene (AAF) is substantially increased if the AAF treatment is followed by prolonged phenobarbital feeding. Our subsequent experiments focused in part on an examination of the characteristics of the tumorigenic enhancement process in liver in an effort to determine whether this experimental system constitutes a valid initiation-promotion model that may be useful for mechanistic studies of multistage tumorigenesis. These investigations involved analyses of the effects on hepatic tumorigenesis of changing the duration of AAF feeding, the duration of phenobarbital feeding, and the interval between the termination of AAF feeding and the onset of phenobarbital feeding. The results demonstrated that the characteristics of the hepatocarcinogenic response to the sequential AAF-phenobarbital treatment protocol are consistent with the classic initiation-promotion model originally derived from studies of skin tumorigenesis.

The present investigation further extends the characterization of the liver initiation-promotion model by comparing the tumor promoting effects of different dietary levels of phenobarbital. When fed at dietary concentrations that did not affect body weight gain, phenobarbital elicited dose-dependent increases in the final incidence (plateau level) of hepatic tumors in rats previously fed AAF. However, these phenobarbital treatments did not affect the time to onset or to cessation (attainment of the plateau phase) of tumorigenesis. The highest dietary concentration of phenobarbital (0.25%) retarded tumor formation initially but ultimately had the strongest promoting effect; rats on this regime also showed a reduction in growth rate. None of the phenobarbital treatments affected the growth rates or the morphological characteristics (degree of differentiation) of the tumors that were produced.

On the basis of the evidence presented it is concluded that (a) phenobarbital has no initiating activity and (b) tumor promotion by phenobarbital involves primarily and increase in the probability that initiated hepatocytes will express the neoplastic phenotype and does not influence the character of this phenotype or the kinetics of its expression.

¹ Supported by the United States Department of Energy under Contract W-31-109-ENG-38.

² Present Address: Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tenn. 37830.

Received 12/11/79. Accepted 6/ 6/80.

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