SYNERGISTIC EFFECTS OF TRANS-4-ACETYLAMINOSTILBENE AND 2-ACETYLAMINOFLUORENE AT THE LEVEL OF TUMOR INITIATION

The synergism of two carcinogenic aromatic amines with different tissu e specificities was studied at the level of initiation in Wistar rats. Gamma-glutamyl transpeptidase and glutathione S-transferase P were us ed as markers for preneoplastic foci in liver. 2-Acetylaminofluorene ( AAF) is a complete rat liver carcinogen, whereas trans-4-acetylaminost ilbene (AAS) produces ear duct tumors quite selectively, but also acts as a strong initiator in rat liver. When these carcinogens were admin istered sequentially as two doses of each or simultaneously as four do ses of a mixture to neonate animals, which then were treated with phen obarbital in the drinking water for promotion, the initiating activity was additive. When these chemicals were given to young adult animals within 4 weeks in two series of four doses, followed by partial hepate ctomy and phenobarbital in the drinking water, the number of preneopla stic foci was greater in groups which had received AAS in both series or in the second series after AAF than in those groups which had recei ved only AAF or AAF in the second series. The average size of foci dep ended clearly on the sequence in which the two carcinogens were admini stered. The foci were larger when AAF was given after AAS. The results support the notion that AAS is a strong initiator in rat liver, and t hat AAF, which is a complete liver carcinogen, has promoting propertie s under certain circumstances in addition to its initiating properties . The two carcinogens seem to produce the initiating lesions independe ntly but the extent of initiation is additive in this model situation. The simplified neonatal rat liver model appears to be particularly su itable for investigating initiating properties and is proposed for stu dies of synergistic effects of genotoxic chemicals on the initiation s tage, independent of organotropism. It avoids a number of complicating factors related to treatment schedule, forced proliferation rate and toxicity in other models.