2-Acetylaminofluorene mechanistic data and risk assessment: DNA reactivity, enhanced cell proliferation and tumor initiation

Verna, Lynne; Whysner, John; Williams, Gary M.

doi:10.1016/0163-7258(96)00063-0

Cited by 78 publications

(35 citation statements)

References 68 publications

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“…Indeed, AAF is a mutagen that is activated through critical enzymatic steps involving cytochrome P450 (CYP1A2). (44) To our knowledge, lanreotide does not interfere with CYP1A2, neither directly nor through growth hormone (GH) inhibition. (45,46) In vitro studies have proposed that somatostatin analogs might control liver cancer cell proliferation by inducing the expression of CdK inhibitors, particularly p27 kip1 (47) and our in vivo data supports this view.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide

et al. 2007

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Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its incidence is increasing worldwide. Due to the known risk factors (mainly hepatitis B and C viruses), we believe there is a rationale for a chemopreventive approach to treat HCC. Here, based on described in vitro data, we evaluated the preventive effects of lanreotide, a somatostatin analog, on the induction of early carcinogenic events. We monitored preneoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in male Wistar rats, using diethylnitrosamine and 2-acetylaminofluorene. Lanreotide was given starting the day after the first diethylnitrosamine injection. By quantitative morphometry, we showed that lanreotide significantly decreases the size of induced preneoplastic foci. Analysis of proliferation and apoptosis assessed by immunohistochemistry, showed decreased proliferation and increased cell death in rats treated with lanreotide. As these events were associated with a significant decreased expression of the cell cycle regulator cyclin D1 and an increased expression of the cyclin-dependent kinase inhibitor p27 kip1 compared to the non-treated group, it is tempting to speculate that these factors are involved in the favorable effect of lanreotide. In conclusion, lanreotide significantly decreases early carcinogenic transformation in a two-step rat model. As lanreotide has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC. (Cancer Sci 2007; 98: 1831-1839) H CC represents a major public health problem. Its incidence is in constant progression, with 2-5 new cases per 100 000 inhabitants/year in western countries and more than 20 per 100 000 inhabitants/year in Asia.(1,2) Curative treatment can only be proposed in 10-20% of cases.The main risk factors of HCC development are cirrhosis and hepatitis B and C that induce genetic alterations leading to preneoplastic, then neoplastic changes. The persistence of infection and/or cirrhosis often leads to tumoral relapse after surgical resection, observed in approximately 20% per year. Therefore, chemoprevention could play an important role in the therapeutic strategy of this disease.In experimental carcinogenesis, preneoplastic foci of altered hepatocytes emerge weeks or months before the appearance of hepatocellular adenomas and HCC.(3) Similar progression has been described in human hepatocarcinogenesis.(4) This fact has led to the development of a number of in vivo systems to study early neoplasia in rat liver.(5) The initiation-promotion or two-stage model of cancer development mimics the early events of the latent period of human carcinogenesis. The initiation stage of cancer development can be produced in rat liver by injection of DEN, (6) a carcinogen that causes DNA ethylation and mutagenesis.(7) Furthermore, DEN has been shown to induce tumors in rodents that closely mimic a subclass of human HCC. Somatostatin analogs (octreotide and lanreotide) are molecules that are widely...

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Section: Discussionmentioning

confidence: 99%

Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide

et al. 2007

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“…Since AAF and DEN are thoroughly studied hepatocarcinogens, which are bioactivated to form DNA adducts in the liver (see reviews in Verna et al, 1996aVerna et al, , 1996b, we have used them to explore differences in the action of DNA-reactive carcinogens at high and low doses, and the possibility of NOELs in a series of dose-response studies of hepatocarcinogenesis in rats (Williams et al, 2000). These experiments are characterized by several features.…”

Section: Introductionmentioning

confidence: 99%

Thresholds for the Effects of 2-Acetylaminofluorene in Rat Liver

2004

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To explore for practical thresholds for DNA-reactive carcinogens in rat liver carcinogenicity, we have conducted a series of exposure-response studies using 2 well-studied hepatocarcinogens, 2-acetylaminofluorene (AAF) and diethylnitrosamine (DEN). Findings with AAF, including as yet unpublished experiments, are reviewed here and related to DEN observations. In these studies, we have administered exact intragastric doses during an initiation segment (IS) of 12-16 weeks followed in some experiments by phenobarbital (PB) as a liver tumor promoter for 24 weeks to enhance manifestation of initiation. The cumulative doses (CD) of AAF at the end of ISs ranged from 0.094 to 282.2 mg/kg. Our findings for AAF in the IS can be summarized as follows: (1) the earliest parameter to be affected with administration of low doses was the appearance of DNA adducts (around 4 weeks), followed at higher doses by cell proliferation; (2) formation of DNA adducts was nonlinear, with a no-observed effect level (NOEL) at a CD of 0.094 mg/kg and a plateau at higher doses (94.1 mg/kg); (3) cytotoxicity (necrosis) showed a NOEL at a CD of 28.2 mg/kg; (4) compensatory hepatocellular proliferation showed a NOEL at a CD of 28.2 mg/kg and was supralinear at a high CD (282.2 mg/kg); (5) formation of preneoplastic hepatocellular altered foci (HAF) showed a NOEL at a CD of 28.2 mg/kg, and was supralinear at a high CD (282.2 mg/kg); (6) a NOEL (CD 28.2 mg/kg) was found for tumor development and the exposure-response was supralinear. We interpret these findings to reflect practical thresholds for hepatocellular initiating effects of AAF and exaggerated responses at high-exposures doses, as also found for DEN. Thus, mechanisms of carcinogenesis can differ between low and high doses.

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“…AAF is a DNA-reactive aromatic amine, which produces mainly liver tumors, particularly in the rat (124). With high exposures, it also produces hepatotoxicity, which can lead to oval cell proliferation (41,112).…”

Section: -Acetylamino Uorene (Aaf)mentioning

confidence: 99%

“…AAF is one of those hepatocarcinogens whose effects are diminished by pretreatment with enzyme inducers (97). This laboratory has been conducting studies of the dose-response of a variety of hepatocellular effects of AAF in male F344 rats (123,131,132), which are highly susceptible to AAF hepatocarcinogenicity (124). The exposures studied ranged from those producing toxicity and promotable neoplastic initiation ( > 395 mg/kg cumulative exposure) to those producing minimal effects and no measurable initiation (40 mg/kg cumulative exposure); the latter exposure is more than 10 times lower than those exposures previously studied by others.…”

Section: -Acetylamino Uorene (Aaf)mentioning

confidence: 99%

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

2002

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Exposure of experimental animals to biologically effective levels of chemicals, either endogenou s or exogenous , the latter of either synthetic or natural origin, elicits a response(s) that re ects the diverse ways in which the various units of organization of an organism deal with chemical perturbation. For some chemicals, an initial response constitutes an adaptive effect that maintains homeostasis. Disruption of this equilibrium at any level of organization leads to an adverse effect, or toxicity. The livers of laboratory animals and humans, like other organs, undergo programmed phases of growth and development , characterized by proliferation followed by differentiation. With organ maturity, the process of differentiation leads to the commitment of differentiated cells to constitutive functions that maintain homeostasis and to specialized functions that serve organismal needs. In the mature livers of all species, proliferation of all cell types subsides to a low level. Thus, the mature liver consists of 2 types of cells: intermediate cells, the hepatocytes , which replicate infrequentl y, but can respond to signals for replication, and replicating cells, the stem cells, endothelial, Kupffer, and stellate cells (Ito or pericytes), bile duct epithelium, and granular lymphocyte s (pit cells). Quanti able alterations or effects at the molecular level underlie alterations at the organelle level, which in turn lead to alterations at the cellular level, which can ultimately be manifested as a change in the whole organism. Alterations can be quantal (binary), either all or none, as with cell replication, cell necrosis or apoptosis, and cell differentiation, which take place at the cellular level. They can also be graded or continuous (nonbinary ), as with enzyme induction, organelle hypertrophy, and extracellular matrix elaboration, occurring either at the intra-or extra (supra) cellular level. Any quanti able change induced in the function or structure of a cell or tissue constitutes a response or effect. Each of the several types of cell in the liver responds to a given stimulus according to its localization and function. Generally, renewing cells are more vulnerable to chemical injury than intermediate cells, which are largely quiescent. Hepatic adaptive responses usually involve actions of the chemical on cellular regulatory pathways, often receptor mediated, leading to changes in gene expression and ultimately alteration of the metabolome. The response is directed toward maintaining homeostasis through modulation of various cellular and extracellular functions. At all levels of organization, adaptive responses are bene cial in that they enhance the capacity of all units to respond to chemical induced stress, are reversible and preserve viability. Such adaptation at subtoxic exposures is also referred to as hormesis. In contrast, adverse or toxic effects in the liver often involve chemical reaction with cellular macromolecules and produce disruption of homeostasis. Such effects diminish the capacity for...

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2-Acetylaminofluorene mechanistic data and risk assessment: DNA reactivity, enhanced cell proliferation and tumor initiation

Cited by 78 publications

References 68 publications

Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide

Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide

Thresholds for the Effects of 2-Acetylaminofluorene in Rat Liver

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

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