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Biomedical subjects

E Farber

Publications and source records attributed to E Farber.

At least 127 records · Page 7Linked to original sources
PubMed1983

Sequential analysis of hepatic carcinogenesis. Regeneration of liver after carbon tetrachloride-induced liver necrosis when hepatocyte proliferation is inhibited by 2-acetylaminofluorene.

The effect of inhibition of hepatocyte proliferation by dietary 2-acetylaminofluorene (2-AAF) on the restoration of liver in rats after a necrogenic dose of carbon tetrachloride has been studied. The liver weights remained low during the entire feeding period of the 2-AAF, and virtually no hepatocyte proliferation was seen, as determined autoradiographically after thymidine incorporation and by the absence of mitotic figures. Oval cell proliferation was extensive. Morphometric analysis showed (a) equal and maximum liver cell necrosis by 24 hours in both the experimental and control groups, (b) similar kinetics of removal of dead liver cells, and (c) similar values for the mean liver cell area. The distance between the portal triad and terminal hepatic vein in animals on the dietary 2-AAF was considerably reduced. Massive hepatocyte proliferation began after termination of the 2-AAF diet, and the liver returned to normal appearance within 14 days. The oval cells disappeared during this period of liver cell restoration. A new hypothesis for oval cell proliferation based on differential inhibition of hepatocyte proliferation resulting in unbalanced growth of ductular cells is presented.

2-Acetylaminofluorene↗
PubMed1983

An experimental method for rapid growth of liver in spleen. The survival and proliferation of chemically induced preneoplastic hepatocytes in spleen.

Cellular suspensions (2 x 10(6) cells) of isolated preneoplastic liver cells, obtained from carcinogen-treated rats, were injected in the spleens of syngeneic rats divided into groups on the basis of no treatment, partial hepatectomy (PH), and/or feeding regimens including 2-acetylaminofluorene (AAF). Recipient rats undergoing both PH and AAF showed significantly more rapid proliferation of the preneoplastic liver cell implant, compared with other treatment groups and control. The theoretic basis for this observation, supported by a large body of data derived from hepatocarcinogenesis, is as follows: The phenotype of the donor cells has been altered by chemical carcinogens such that the liver cells develop resistance to growth-inhibiting agents such as AAF. The recipient receives PH and AAF, the former creating a strong proliferative stimulus for hepatocytes, while the latter inhibits regeneration of normal liver cells but not those resistant to the mito-inhibitory effect of AAF, ie, the carcinogen-altered donor cells. These manipulations in donors and recipients thus create a selective environment in which the implant undergoes rapid proliferation. This model of resistance induction followed by selective proliferation, built upon the principles of carcinogenesis and applied to isolated liver cell transplantation, provides an experimental basis for achieving rapid liver growth of the splenic implant.

2-Acetylaminofluorene↗
PubMed1982

Kinetics of phenotypic maturation of remodeling of hyperplastic nodules during liver carcinogenesis.

Hyperplastic nodules appearing during the preneoplastic phase of liver carcinogenesis were divided into two types, persistent and remodeling, according to the pattern of staining for gamma-glutamyltransferase. In the resistant cell model of liver carcinogenesis used in this study, hyperplastic nodules, uniformly staining for gamma-glutamyltransferase, rapidly emerge by 4 weeks after a single injection of diethylnitrosamine and brief selection by dietary 2-acetylaminofluorene plus partial hepatectomy. By 6 weeks, a majority of nodules (about 75%) show an obvious irregularity and loss of uniformity in staining for gamma-glutamyltransferase while the remaining nodules continue to be uniformly stained. The number of irregularly stained nodules increases over the next 18 weeks until over 95% of nodules show the nonuniform loss of enzyme activity. The progressive loss of enzyme activity is accompanied by architectural remodeling to normal-appearing liver. This is associated with the increasing disappearance of many obvious nodules from the liver as the remodeling ones blend imperceptibly with the surrounding liver. The uniformly stained nodules show the persistence of hepatocyte arrangements in plates two or more cells thick and in acini and of cytoplasmic hypertrophy characteristic of persistent hyperplastic nodules. Labeling indices are much higher in hepatocytes of the persistent uniformly stained nodules than in the remodeling ones. The possibility of exploiting this phase of the model further for in-depth analysis of the nodule-to-carcinoma sequence is discussed.

2-Acetylaminofluorene↗
PubMed1982

Effects of delays in the cell cycle on the induction of preneoplastic and neoplastic lesions in rat liver by 1,2-dimethylhydrazine.

This study was designed to explore further the relationship between cell proliferation and the induction of early putative preneoplastic lesions by carcinogens. Rats were given a non-necrogenic dose of 1,2-dimethylhydrazine 24 hr before being subjected to partial hepatectomy. Beginning 4 hr later, hydrocortisone was injected 10 times at 4-hr intervals to delay progression through the cell cycle, including inhibition of DNA synthesis by at least 85% for about 40 hr. At the appropriate time thereafter, the putative preneoplastic hepatocytes were selectively stimulated to grow in vivo into gamma-glutamyltransferase-positive focal lesions. Animals given hydrocortisone showed a large decrease (71%) in the number of gamma-glutamyltransferase-positive foci. In contrast, when hydrocortisone was given at 6 days after partial hepatectomy, no inhibition in the induction of hepatic lesions was observed. In the next experiments, rats were treated with 1,2-dimethylhydrazine and were subjected to partial hepatectomy at 12, 24, or 48 hr or 1 week thereafter. A significant number of gamma-glutamyltransferase-positive foci was found when partial hepatectomy was performed at 12 or 24 hr but far fewer were found when the operative partial hepatectomy was delayed to 48 hr or 1 week later. Similarly, in long-term experiments, six of 14 animals developed primary hepatocellular carcinoma 13 months after the time of injection of 1,2-dimethylhydrazine when partial hepatectomy was performed at 12 hr, while none of the animals developed liver cancer when the operation was performed at 48 hr. These results imply that the majority of biochemical lesions induced by 1,2-dimethylhydrazine that are relevant to the induction of liver preneoplasia and neoplasia are short-lived and that their persistence is associated with some cellular activity closely related to the cell cycle.

Animals↗
PubMed1981

The sequential analysis of cancer induction with chemicals.

A critical review of some of our current views on how chemicals induced cancer is presented. Emphasis is placed on pathologic processes, rather than on agents and on the many steps that lie between initial exposure to a carcinogen and the appearance of malignant neoplasia. The nature of some of the early steps in carcinogenesis is outlined including the early appearance during initiation of cells resistant to some of the inhibitory effect of carcinogens. This property is considered to be important in the development of cancer in at least one model of carcinogenesis. The essential characteristic of promotion, differential stimulation of proliferation of initiated cells, is discussed along with at least three possible mechanisms for such differential effects of promoting environments. The multistep hypothesis for cancer development is supported by observations of identifiable biochemical and biological properties of different cell populations at some steps. The implications of this for cancer diagnosis, prevention and control are briefly discussed.

Animals↗
PubMed1981

Role of acute hepatic necrosis in the induction of early steps in liver carcinogenesis by diethylnitrosamine.

Experiments were performed to assess the role of liver cell necrosis in the induction of early steps in liver carcinogenesis with diethylnitrosamine, as measured by the appearance of foci of resistant hepatocytes that stain for gamma-glutamyl transpeptidase and that are presumptive preneoplastic lesions in the rat. With the use of a necrogenic dose of diethylnitrosamine and an assay for the carcinogen-induced early stages or resistant hepatocytes, the number of enzyme-altered foci was decreased to a major extent (up to 62%) by posttreatment with diethyldithiocarbamate, a derivative of disulfiram. Such posttreatment decreased to a large degree (78%) the cumulative labeling index of hepatocytes following an initial exposure to diethylnitrosamine. The performance of partial hepatectomy up to 68 hr after such posttreatment restored the level of induction of the resistant hepatocytes. Nonnecrogenic doses of diethylnitrosamine or dimethylnitrosamine induced virtually no foci of resistant hepatocytes but did so when coupled with cell proliferation. These results establish clearly an important role for liver cell necrosis in the production of early steps in liver carcinogenesis in one model. The mechanism for this effect appears to be by the induction of compensatory liver cell proliferation.

Animals↗
PubMed1981

Some conclusions derived from a liver model for carcinogenesis.

A new model of liver cancer development with chemicals is described. This model was based on the hypothesis that chemical carcinogens induced as a first step altered hepatocytes that are resistant to the inhibitory effect of a carcinogen, such as N-2-fluorenylacetamide, on cell proliferation. After the administration of a single initiating dose of a carcinogen, the rare resistant hepatocyte is selected by the creation of a special selection pressure, consisting of a stimulus for cell proliferation in the presence of an environment that inhibits normal hepatocyte proliferation. The latter is created by brief exposure to dietary N-2-fluorenylacetamide. With this approach, initiated hepatocytes and large hyperplastic liver nodules can be rapidly induced in a synchronized fashion. A direct material continuity between resistant hepatocytes, foci, and nodules of such cells (hyperplastic nodules) and hepatocellular carcinoma was established with diethylnitrosamine as the initiating carcinogen. The use of the resistant cell model has shown that initiation consisted of at least two steps, the second of which is a compulsory round of cell proliferation. With this model, three mechanisms of promotion in the liver are suggested: differential inhibition, differential stimulation, and differential recovery. The relationship of these early changes to liver cancer development is discussed.

Animals↗
PubMed1980

Resistant hepatocytes as early changes in liver induced by polycyclic aromatic hydrocarbons.

Induction of putative preneoplastic hepatocytes which are resistant to cytotoxic effect of 2-acetylaminofluorene (2-AAF) by five carcinogenic polycyclic aromatic hydrocarbons (PAH) was tested using gamma-glutamyl transpeptidase (gamma-GT) as a histochemical marker enzyme. Benzo (a) pyrene [B(a)P], 7,12-dimethylbenz(a) anthracene (7,12-DMBA), 3-methylcholanthrene (3-MC), dibenz (a,h)-anthracene [DB(a, h)A] and benzo (a) anthracene [B(a)A] were given 12 h after partial hepatectomy (PH) followed by 2-AAF and carbon tetrachloride (CCI4) feeding, a procedure developed by this laboratory. All of the five PAHs induced a signficantly increased number of gamma-GT positive foci when compared with sham-hepatectomized (SH) or vehicle control groups. The numbers of gamma-GT-positive foci induced by B(as)P, 7,12-DMBA, 3-MC and DB (a,h)A were significantly different from all of the parent compounds, anthracene, naphthalene, pyrene and phenanthrene. B(a)A did not induce significantly increased number of foci only when compared to anthracene. Possible usefulness of this system for in vivo short-term assay is discussed.

Animals↗
PubMed1980

Toxicological significance of liver hypertrophy produced by inducers of drug-metabolizing enzymes.

Changes in enzyme activity due to induction by chemicals is an important property that can determine the type of response seen in tissues exposed to environmental chemicals. Two major types of response, acute irreversible liver cell injury or death (necrosis) and long-term cancer induction, are discussed in terms of their modulation by enzyme induction. Most commonly, enzyme induction leads to a more severe toxic response by the liver, and to more cell death. However, inducers may have a protective effect, especially in carcinogenesis, when they most frequently protect against cancer induction if used early in the process. There is a discrepancy between this observation and the increase in mutagenic activity of liver preparations observed after induction. However, when enzyme induction occurs at a later stage, after initiation, it often accelerates or promotes cancer induction. Also, new cell populations constantly observed during liver carcinogenesis are composed of very hypertrophic hepatocytes containing a large amount of smooth endoplasmic reticulum. This is associated with a radical change in enzyme activities in the reticulum, which may account in part for the characteristic resistance exhibited by initiated cells to hepatotoxins and carcinogens. The resistance is considered to be an important property that may play a key role in the development of cancer under some circumstances.

Animals↗