4-acetylaminostilbene and Precancerous-Conditions

The synergism of two carcinogenic aromatic amines with different tissue specificities was studied at the level of initiation in Wistar rats. Gamma-glutamyl transpeptidase and glutathione S-transferase P were used as markers for preneoplastic foci in liver. 2-Acetylaminofluorene (AAF) is a complete rat liver carcinogen, whereas trans-4-acetylaminostilbene (AAS) produces ear duct tumors quite selectively, but also acts as a strong initiator in rat liver. When these carcinogens were administered sequentially as two doses of each or simultaneously as four doses of a mixture to neonate animals, which then were treated with phenobarbital 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 hepatectomy and phenobarbital in the drinking water, the number of preneoplastic 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 received only AAF or AAF in the second series. The average size of foci depended clearly on the sequence in which the two carcinogens were administered. 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 that AAF, which is a complete liver carcinogen, has promoting properties under certain circumstances in addition to its initiating properties. The two carcinogens seem to produce the initiating lesions independently but the extent of initiation is additive in this model situation. The simplified neonatal rat liver model appears to be particularly suitable for investigating initiating properties and is proposed for studies of synergistic effects of genotoxic chemicals on the initiation stage, independent of organotropism. It avoids a number of complicating factors related to treatment schedule, forced proliferation rate and toxicity in other models.

Topics: 2-Acetylaminofluorene; Aging; Animals; Biomarkers, Tumor; Carcinogens; Drug Synergism; Female; gamma-Glutamyltransferase; Glutathione Transferase; Hepatectomy; Liver; Liver Neoplasms; Male; Phenobarbital; Precancerous Conditions; Rats; Rats, Wistar; Sex Factors; Stilbenes; Time Factors

Two carcinogenic aromatic amines with different organotropism were tested for syncarcinogenic effects in rat liver in an initiation-promotion experiment. Trans-4-acetylaminostilbene (AAS) and 2-acetylaminofluorene (AAF) were administered as initiators in four doses each either alone or sequentially combined in both orders. The promotion phase was started by partial hepatectomy and continued by adding phenobarbital (250 p.p.m.) to the drinking water for 26 weeks. The number/cm2 of tissue section and average size of hyperplastic foci, glucose-6-phosphatase-deficient and gamma-glutamyl-transpeptidase-positive foci were determined and a total area of lesions calculated during the promotion phase after 18 and 31 weeks, and in the post-promotion phase after 42 and 47 weeks. The synergistic effects of AAS and AAF were clearly more than additive if compared with the sum of the effects exerted by each compound individually. The sequence in which both initiators were administered remarkably influenced the development of lesions. They developed more rapidly and persisted longer in the post-promotion phase when AAS was administered first and AAF second. In the final stage, enzyme altered foci increased in the livers of both combination groups, but to a greater extent in the AAS-AAF group. It is concluded that the two arylamides damage DNA independently. In addition, however, the results suggest that AAS acts predominantly as an initiator, and AAF as a weak initiator and a strong promoter in what is considered the initiation phase of this experiment.

Topics: 2-Acetylaminofluorene; Animals; Carcinogens; Cocarcinogenesis; DNA; Female; Liver Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Stilbenes

After repeated administration of trans-4-acetylaminostilbene to rats, DNA-bound metabolites accumulate to the greatest extent in liver and kidney, which are considered to be nontarget tissues for this carcinogen. To test whether the persistent DNA adducts represent procarcinogenic lesions, an initiation-promotion experiment was carried out using trans-4-acetylaminostilbene as an initiator and phenobarbital, DDT and diethylstilbestrol as promoters. In addition, partial hepatectomy was performed in some groups. Partial hepatectomy alone or in combination with promoters led to the formation of preneoplastic enzyme deficient foci, hyperplastic nodules and hepatoma in great yields. In addition, mammary tumors were observed with diethylstilbestrol promotion. The results support our proposal that aminostilbene derivatives produce procarcinogenic DNA-lesions in many, if not all, tissues and that secondary factors determine when and where tumors arise.

Topics: Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Body Weight; Carcinogens; DNA; Female; Hyperplasia; Liver; Liver Neoplasms, Experimental; Liver Regeneration; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Stilbenes