Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine

Pitot, Henry C.; Barsness, Lona; Goldsworthy, Thomas L.; Kitagawa, Tomoyuki

doi:10.1038/271456a0

Cited by 361 publications

(121 citation statements)

References 13 publications

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“…5-azacytidine was administered once only at day 21 to timed pregnant rats at a dose of 10mg kg (Regimen 11) or once only at a dose of 5 mg kg to weanling rats (Regimen 12). In order to determine whether 5-azacytidine had hepatic tumour promoting activity, rats were administered a liver cancer initiating dose of diethylnitrosamine 30 mg kg-1 administered 18 h after a partial hepatectomy, after the regimen of Pitot et al (1978), and were then given chronic 5-azacytidine 2.5 mg kg-1 i.p. as in regimen 2.…”

Section: Statistical Evaluation Of Resultsmentioning

confidence: 99%

“…In the group of rats that received a single initiating dose of the liver carcinogen DEN (Regimen 13, Table II), all the surviving rats developed hyperplastic liver nodules and a high incidence of non-hepatic, non-testicular primary tumours. Previous work has established that low single DEN doses after a two-thirds partial hepatectomy do not result in liver tumours without subsequent tumour promotion (Carr et al, 1984;Pitot et al, 1978). Tetrahydrouridine control rats did not develop any excess of non-testicular tumours nor did they show testicular atrophy (Regimen 14).…”

Section: Carcinogenicitymentioning

confidence: 99%

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Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

Carr

Rahbar²,

Asmeron³

et al. 1988

Br J Cancer

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Summary We investigated 5-azacytidine and five of its analogues for: (1) carcinogenicity, in the male Fischer rat; (2) toxicities using changes in rat weights in vivo and a cytotoxicity assay in vitro; and (3) haemoglobin gene expression, using minor haemoglobin synthesis in sheep, mice and rats. 5-Azacytidine was found to be a complete carcinogen. It increased the incidence of testicular tumours as well as non-testicular tumours in rats treated for 12 months. 5-Azacytidine also had hepatic tumour promoting properties and was able to induce transplacental carcinogenesis when administered to pregnant rats on day 21 of timed pregnancies. None of the other 5 analogues that were tested appeared to be carcinogenic in small experiments. All the analogues which are known to have hypomethylating activity were found to be cytotoxic in vitro; the most potent being 5-azacytidine. As judged by decreased rat weight compared to untreated controls, the fluorinated cytidine analogues and 5'-deoxyazacytidine were more toxic than 5-azacytidine. Altered haemoglobin synthesis was seen in rats and DBA/2J mice, but not in sheep. In mice, where the clearest haemoglobin changes were noted, an increase in minor haemoglobin synthesis was found using both high and low doses of 5-azacytidine, and with 5,6-dihydro-5-azacytidine and 5-aza-2'-deoxycytidine. These last two analogues appear to be relatively non-toxic, noncarcinogenic in these experiments, and retain haemoglobin activating properties with a potency similar to that of 5-azacytidine.Enzymatic DNA methylation occurs as a postreplicative process, producing, in mammals, only the minor base 5-methylcytosine. The methylation of specific DNA cytosine residues is inversely correlated with transcription of most genes, although there are exceptions. Inhibitors of DNA methylation will often activate previously silent genes and this is the strongest single line of evidence implicating methylation in gene control. There have been several recent reviews of mammalian DNA methylation (Holliday, 1979;

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Section: Statistical Evaluation Of Resultsmentioning

confidence: 99%

Section: Carcinogenicitymentioning

confidence: 99%

Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

Carr

Rahbar²,

Asmeron³

et al. 1988

Br J Cancer

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“…Much attention has been focused on the morphological, histological and biochemical properties of preneoplastic lesions such as enzyme-altered foci and hyperplastic nodules induced at the early stages of chemical hepatocarcinogenesis (Pitot et al, 1978;Farber and Cameron, 1980). One of the enzymes altered in early hepatocarcinogenesis is GST-P.…”

Section: Discussionmentioning

confidence: 99%

Potential effect of Nigella sativa against Diethylnitrosamine-induced hepatocarcinogenesis in rats

Ahmed

Brellou

Gameel

et al. 2017

J Hellenic Vet Med Soc

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Objective of the investigation was the study of potential protective effects of the watery extract of Nigella sativa against diethylnitrosamine induced hepatocarcinogenesis in rats. N. sativa was administered to rats for protection against diethylnitrosamine-induced hepatocarcinogenesis. It was administered prior to, simultaneously with or after injection of diethylnitrosamine. Five groups of Wister rats were used. Group A was administered diethylnitrosamine and N. sativa simultaneously, group B was administered only diethylnitrosamine and group C received only N. sativa. These three groups were maintained for up to eight weeks. Group D received N. sativa six weeks after administration ofdiethylnitrosamine,while group E (“protective group”) received N. sativa on day 1 and diethylnitrosamine six weeks later. These two groups were maintained for up to 12 weeks. All rats were subjected to partial hepatectomy to enhance carcinogenesis. P-isoform of glutathione s transferase (GST-P) was detected in the cytoplasm and nuclei of hepatocytes. The number of GST-P positive foci was significantly smaller in test groups (A, D, E), particularly in groups A and E, when compared with to those in group B, indicating that N. sativa has protective effects against diethylnitrosamine induced liver cancer in rats, even in the very early stages of hepatocarcinogenesis.

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“…A similar regenerative growth can be observed in the liver after treatment with several chemicals, including many carcinogens, that induce cell necrosis. This type of cell proliferation, called compensatory regeneration, is positively correlated with the initiation phase of chemical hepatocarcinogenesis (5)(6)(7)(8) (18,19) or the orotic acid (OA) model (20). Thus, it appears that only compensatory liver cell proliferation, but not direct hyperplasia, supports carcinogen-induced initiation.…”

Section: Compensatory Regenerationmentioning

confidence: 99%

Compensatory Regeneration, Mitogen-Induced Liver Growth, and Multistage Chemical Carcinogenesis

Ledda-Columbano¹,

Coni²,

Simbula³

et al. 1993

Environmental Health Perspectives

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Liver cell proliferation has often been implicated to play a major role during different steps of the carcinogenic process. Most of the experimental studies indicating a close association between cell proliferation and liver cancer development have made use of a compensatory type of proliferative stimulus. However, liver growth may also be caused by direct hyperplasia after administration of primary mitogens. Our recent studies examined the possible differences between these two types of cell proliferation. Our studies indicate that a) increased expression of proto-oncogenes such as c-fos, c-jun, and c-myc is not necessary for entry into the cell cycle during mitogen-induced liver growth; b) mitogen-induced liver growth does not support initiation of chemical hepatocarcinogenesis; c) repeated proliferative stimuli induced by primary mitogens do not stimulate the growth of initiated cells to a focal and/or nodular stage; and d) mitogen-induced liver growth, unlike compensatory regeneration, is followed by a particular mode of cell death, namely, apoptosis. This type of cell death may be responsible for the elimination of carcinogen-initiated cells.

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Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine

Cited by 361 publications

References 13 publications

Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

Potential effect of Nigella sativa against Diethylnitrosamine-induced hepatocarcinogenesis in rats

Compensatory Regeneration, Mitogen-Induced Liver Growth, and Multistage Chemical Carcinogenesis

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