4-acetylaminostilbene and Cocarcinogenesis

It has been demonstrated in several model systems that tumors arise in a multistage process. Carcinogenic aromatic amines are complete carcinogens, which usually produce tumors in typical target tissues without any additional treatment. The tissue specificity, however, cannot readily be explained by genotoxic effects, and the role of secondary effects is not well understood. Promotional pressure on initiated cells can be produced by endogenous factors but also by the chemical itself. Comparison of the effects on rat liver of 2-acetylaminofluorene (AAF) and trans-4-acetylaminostilbene (AAS) provides some evidence that initiating and promoting properties of these chemicals can be separated. AAS is a strong initiator in rat liver but seems to lack promoting activity; AAF is a less efficient initiator but has tumor promoting properties. The results obtained so far indicate that promoting pressure is not produced by the acute, cytotoxic effects of AAF. It is therefore concluded that nongenotoxic, possibly receptor-mediated effects are involved.

Topics: 2-Acetylaminofluorene; Amines; Animals; Carcinogens; Cocarcinogenesis; DNA; Drug Synergism; Genes; Liver Neoplasms, Experimental; Rats; Stilbenes

trans-4-Acetylaminostilbene (AAS) is a complete carcinogen in rats and produces quite selectively tumors in Zymbal's glands. On the basis of DNA adduct formation, it has been proposed that this model arylamine initiates neoplastic transformation of cells in many tissues, particularly liver and kidney, which, in the classical sense are considered to be non-target tissues for this chemical. In the present study an initiating treatment with AAS was followed by unilateral nephrectomy and the application of two nephrotoxic substances, gentamycin or beta-cyclodextrin which, among other activities, stimulate cell proliferation specifically in kidney. The initiating dose of AAS, given alone, gave rise to Zymbal's gland and mammary tumors in female Wistar rats within 88 weeks but not to liver or kidney tumors. When the initiation treatment was followed by unilateral nephrectomy, alone or in combination with gentamycin, or by beta-cyclodextrin, four tumors in two out of ten animals, eight tumors in three/ten, and seven tumors in three/ten, respectively, were observed in the kidney. The administered dose of gentamycin was not sufficient to induce tumors on its own. The results support the view that the genotoxic effects of AAS produce promotable lesions in rat kidney. None of the animals that had been treated with AAS, with or without other treatments, developed tumors or the predominant types of preneoplastic lesions in the liver within 88 weeks; this supports the notion that liver, like kidney, is not a target for complete carcinogenesis for this chemical.

Topics: Adenoma, Chromophobe; Animals; beta-Cyclodextrins; Carcinogens; Cocarcinogenesis; Cyclodextrins; Cystadenoma; Female; Gentamicins; Kidney Neoplasms; Nephrectomy; Rats; Rats, Wistar; Stilbenes

Both trans-4-acetylaminostilbene (AAS) and 2-acetylaminofluorene (AAF) exert tumor-initiating activity in rat liver when administered in the initiation phase of an initiation-promotion experiment. The effects are more than additive when the compounds are sequentially combined in the initiation phase of such an experiment, and this synergism is more pronounced when AAS is given first, followed by AAF, than vice versa. In order to determine the role of target DNA dose, [3H]AAS and [14C]AAF were administered to female Wistar rats adhering to the protocol of the initiation phase of the above-mentioned experiment and the following parameters measured at the end of this phase: total radioactivity in tissues, binding to DNA, RNA and proteins in liver, adduct pattern in liver DNA and RNA. In neither combination were these parameters significantly different from those in the appropriate controls in which only one of the compounds was administered. This result indicates that combining the substances did not alter the pharmacokinetics of the individual compounds and that the target dose is additive. This suggests that effects unrelated to DNA binding, possibly promoting effects, may cause the more than additive generation of preneoplastic lesions in rat liver.

Topics: 2-Acetylaminofluorene; Animals; Cocarcinogenesis; DNA Damage; DNA, Neoplasm; Drug Synergism; Female; Hydrolysis; Liver Neoplasms, Experimental; Rats; Rats, Inbred Strains; Stilbenes

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