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Biomedical subjects

E Farber

Publications and source records attributed to E Farber.

At least 73 records · Page 4Linked to original sources
PubMed1987

Alternative methods of selecting rat hepatocellular nodules resistant to 2-acetylaminofluorene.

Dietary 2-acetylaminofluorene (2-AAF) coupled with a stimulus for cell proliferation such as a 2/3 partial hepatectomy (PH) or a necrotizing dose of carbon tetrachloride is frequently employed to generate nodules of resistant ("initiated") rat hepatocytes. This regimen is a useful model for experimental analysis of alterations in hepatocytes during carcinogenesis, and also as an assay for initiation by various carcinogens. Because of the decreasing availability of carcinogen-containing diets from commercial sources, we have developed alternative methods of 2-AAF administration to generate nodules in rats initiated with N-nitrosodiethylamine. This study compared the nodule-selecting and cancer-promoting efficacy of 2-AAF administered by the Solt-Farber procedure (0.02% in diet for 2 weeks) with 2-AAF administered by gavage, as a suspension in 1% aqueous carboxymethyl-cellulose (CMC). Three or 4 daily administrations of 2-AAF by gavage (20 mg/kg/day) followed by PH on day 4 were equivalent to the dietary regimen in generating early resistant nodules, late persistent nodules and hepatocellular carcinomas. These regimens were similar to the dietary regimen of 2-AAF in inhibiting virtually all normal hepatocyte proliferation. These regimens permit control over the duration and level of 2-AAF exposure and the resulting size of selected nodules.

2-Acetylaminofluorene↗
PubMed1987

Mitogenic activity in platelet-poor plasma from rats with persistent liver nodules or liver cancer.

Platelet-poor plasma (PPP) from F-344 rats with chemically-induced preneoplastic liver nodules or hepatocellular carcinoma stimulated S-phase DNA synthesis in monolayer cultures of normal rat hepatocytes. Similar mitogenic activity was detected in PPP 6 hrs to 1 week after partial hepatectomy (PH) or after necrotizing doses of CCl4 or diethylnitrosamine (DENA). Very little activity was found in PPP4 from control rats. The mitogenic activity in PPP from animals with nodules was non-dialyzable (greater than 14 kd) and bound to a heparin-sepharose affinity column. None of the mitogenic PPPs competed with [125I] epidermal growth factor (EGF) for binding sites on A431 cells or normal rat hepatocytes. These studies indicate that persistent proliferation of preneoplastic and neoplastic hepatocytes is associated with increased circulating levels of mitogenic hepatocyte growth factor.

Animals↗
PubMed1987

Progression in hepatocarcinogenesis: differences in growth and behavior of transplants of early and later hepatocyte nodules in the rat spleen.

Hepatocyte nodules were induced in Fischer 344 rats using the resistant hepatocyte model. Nodules harvested at 5, 24, or 25 weeks after initiation were isolated, diced, and transplanted into the spleen of normal rats and observed for periods up to 104 weeks. In the first experiment, 50% of the animals developed hepatocellular carcinoma, some with invasion and metastasis, by 70 to 104 weeks. In the second experiment, transplants of 5-week nodules grew very slowly and diffusely in the spleen, as did normal liver, but retained at least some of their phenotypic properties. In contrast, transplants of 25-week nodules grew into nodules up to 2.5 cm in diameter by 70 weeks. Two of the larger nodules had smaller nodules within resembling trabecular carcinoma. Transplants from the liver surrounding the 25-week nodules did not grow and produced no nodules by 70 weeks after transplantation. The implications of these observations in the study of progression in hepatocarcinogenesis are discussed briefly.

Animals↗
PubMed1987

Patterns of ligand binding to normal, regenerating, preneoplastic, and neoplastic rat hepatocytes.

The binding of epidermal growth factor, asialoorosomucoid, and apoprotein E-rich lipoproteins to isolated hepatocytes was investigated at various time intervals during the step-by-step development of liver cancer in rats. The degree of binding of the three ligands showed a progressive reduction in early persistent and late persistent putative preneoplastic hepatocyte nodules. This was further decreased in hepatocytes isolated from unequivocal hepatocellular carcinomas. Regenerating liver hepatocytes bound lesser amounts of epidermal growth factor and asialoorosomucoid than did hepatocytes from control resting liver but increased amounts of apoprotein E-rich lipoproteins. The progressive decrease in ligand binding during the precancerous phase of hepatocarcinogenesis, the nodule-to-cancer sequence, may render nodules less responsive to the influences of their external environments.

Animals↗
PubMed1987

Influences of diethylnitrosamine on longevity of surrounding hepatocytes and progression of transplanted persistent nodules during phenobarbital promotion of hepatocarcinogenesis.

The possibility that phenobarbital (PB) selectively promotes liver nodule development by decreasing survival of surrounding hepatocytes previously exposed to diethylnitrosamine (DENA) was evaluated. Livers of F-344 rats were labelled with [3H-methyl]-thymidine (3H-TdR) during developmental or regenerative growth. Neonatal rats given 3H-TdR between days 3 and 12 were subjected at 12 weeks of age to partial hepatectomy (PH) followed 24 hr later by DENA (10 mg/kg) or saline. Subsequent administration of PB (0.1% in drinking water) for 28 weeks reduced total liver label to 46 +/- 10% (saline group) or 40 +/- 4% (DENA group). Adult male rats initiated with DENA (200 mg/kg) and later labelled with 3H-TdR after PH also lost total liver label during 28 weeks' promotion with PB (0.05% in water) at rates similar to those exhibited by noninitiated rats given PB, and by DENA-treated or control rats not given PB. Large persistent (12 weeks) liver nodules generated by DENA in the Solt-Farber model were transplanted as small fragments into the spleens of syngeneic rats previously given 0, 100 or 200 mg/kg of DENA. Subsequent exposure to PB (0.05% in drinking water for 40 weeks) or Aroclor 1254 (6 X 300 mg/kg per month) promoted nodule and cancer development only in livers of DENA-initiated recipients. Surviving transplanted nodules remained as small microscopic clusters even after 40 weeks of promotion. However, PB increased transplant survival (50% vs. 21% in controls) whereas Aroclor reduced it to 8%. These findings indicate that promotion of liver nodules by PB occurs without enhanced mortality of surrounding hepatocytes previously damaged by DENA. They further suggest that promoters such as PB and PCBs do not directly influence the progression of established persistent nodules.

Animals↗
PubMed1987

Identification of a characteristic cytosolic polypeptide of rat preneoplastic hepatocyte nodules as placental glutathione S-transferase.

Evidence is presented that a distinctive type of glutathione-S-transferase (GSHTase-P), and a cytosolic polypeptide of Mr 52,000 (P-52), each appearing in greatly increased amounts in hepatocyte nodules during liver carcinogenesis in the rat, are so far indistinguishable. The probable identity of the two polypeptides was established with the use of SDS polyacrylamide gel electrophoresis and Western blot techniques with purified GSHTase-P and P-52 and their respective antibodies and by comparison of the sequence of the first 26 N-terminal amino acids. Since the enzyme and the polypeptide are each considered to be the best available early markers for hepatocyte nodules, as putative precancerous lesions, their probable identity makes them attractive cellular components for in depth studies on their transcriptional and translational regulation and their use in new approaches to the sequential analysis of liver carcinogenesis.

Amino Acid Sequence↗
PubMed1987

Pathogenesis of experimental liver cancer: comparison with humans.

The multi-step nature of cancer development in the liver with chemical carcinogens is very well developed in the rat and is highly probable in humans and in mice. Since this step-by-step analysis of hepatocarcinogenesis is much more advanced in the rat than in the other two species, the pathogenesis in the rat will be briefly reviewed. Initiation steps I and II, promotion steps III and IV and progression steps V and VI will be highlighted together with further unknown steps in progression to cancer. The focal proliferation of hepatocytes, as represented by hepatocyte nodules, appears to play a central and critical role as a precursor for cancer. In the rat, nodules have a very characteristic phenotype biologically, histologically and biochemically. Some of the options available to nodules and their significance will be discussed. The possible analogy between rat on the one hand and mice and humans on the other will be presented. A critical assessment of the relevance of pathological changes seen in rats and mice to the possible carcinogenicity of agents in humans will be discussed. The urgent need for more step-by-step studies of hepatocarcinogenesis in mice is very obvious and must be stressed.

Animals↗
PubMed1987

Initiation of carcinogenesis by a dietary deficiency of choline in the absence of added carcinogens.

The feeding for 10 or 11 weeks of young male Fischer-344 rats, a diet devoid of choline and low in methionine, leads to the appearance of gamma-glutamyltransferase-positive foci of altered hepatocytes in the liver and to the induction of initiated resistant hepatocytes. The latter are known to contain the primary precursor cells for the ultimate development of hepatocellular carcinoma. This initiation of carcinogenesis with the choline-devoid diet is prevented by added choline. These observations indicate that a dietary deficiency may, by itself, without known contaminating or added carcinogens, initiate the carcinogenic process.

Animals↗
PubMed1987

Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas.

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development of MDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a well-studied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3- to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a greater than 80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.

2-Acetylaminofluorene↗
PubMed1987

Modulation of calcium by the carcinogenic process in the liver induced by a choline-deficient diet.

A diet devoid of choline and low in methionine (CD), without any added carcinogen, has been shown to induce 100% preneoplastic nodules and more than 50% cancer in the rat liver. Attempts to understand the mechanism by which a CD diet induces liver cell cancer revealed that like chemical carcinogens, a CD diet also appears to cause alterations in DNA, perhaps mediated by free radicals. Indeed, a CD diet induces nuclear lipid peroxidation prior to the changes in DNA. The CD diet induced DNA alterations coupled with continuing liver cell proliferation may account for the induction of initiated hepatocytes by the CD diet. To gain insight into the nature of free radicals generated by the CD diet, experiments were designed to determine whether agents that modulate free radical effects influence the CD diet induced changes in the liver. We investigated the effect of Ca2+ in the modulation of CD diet induced alterations in the liver. The results show that extra Ca2+ when added to the CD diet prevented some of the early changes due to choline deficiency, such as nuclear lipid peroxidation and DNA damage, but had little or no effect on the triglyceride accumulation in the liver. Also, the same CD diet with extra Ca2+, when used as a promoter after initiation by diethylnitrosamine, decreased the number and size of early putative preneoplastic foci and nodules.

Animals↗
PubMed1987

Possible etiologic mechanisms in chemical carcinogenesis.

Some highlights in the development of our knowledge about carcinogens as etiological agents for cancer are reviewed briefly. Advances during the past 20 years relating to metabolic activation with the genesis of reactive metabolites, molecular targets and their interactions with activated carcinogens, oncogenes as molecular targets and the dependence on cell proliferation, all relating to the initiation process, are reviewed. Critical to initiation is the new phenotype in the initiated cell, known only in one instance, the rat liver, in which the characteristic change is one of resistance to many xenobiotic influences. The need for clonal expansion of initiated cells as essential for carcinogenic effects is discussed. Differential inhibition has been shown as a dominant mechanistic pattern in the liver. In other systems, the manner in which clonal expansion is achieved is not evident. The need for studies of the processes involved in carcinogenesis, as well as the agents, is emphasized, in view of the continuing validity of the cell concept as the key to integrating the increasingly large volume of data from the molecular with the biological.

Animals↗
PubMed1987

Experimental induction of hepatocellular carcinoma as a paradigm for carcinogenesis.

The current status of our understanding of the step-by-step development of cancer in the liver in the rat, initiated with chemical carcinogens, is reviewed briefly. The carcinogenic process consists of a sequence of changes in rare hepatocytes, some of which become evident by clonal expansion to form nodules, separated by long periods of progressive change in gene expression. Cell proliferation is important in initiation, in promotion and in progression as well as in cancer per se. Some of the known mechanisms for initiation, promotion and progression are briefly reviewed. The apparent similarity between the process of cancer development in the experimental animal and in the human is emphasized. The possible relation of the process to oncogenes and growth factors is discussed briefly.

Animals↗
PubMed1986

Ethionine in the analysis of the possible separate roles of methionine and choline deficiencies in carcinogenesis.

The importance of ethionine, the ethyl analogue of methionine, as a metabolic probe to study the possible roles of methionine and choline in liver carcinogenesis has been briefly reviewed. Ethionine-induced liver carcinogenesis is similar in many aspects, including initiation, promotion, and progression, to carcinogenesis with other agents. However, the special role of methionine in preventing virtually all metabolic and pathologic effects of ethionine, including liver cancer, places ethionine in a special position. On the basis of these observations and our current knowledge about choline deficiency in the genesis of liver cancer, we proposed that choline and methionine play separate but overlapping roles in the initiation and promotion of liver carcinogenesis.

Animals↗
PubMed1986

A choline-devoid diet, carcinogenic in the rat, induces DNA damage and repair.

A diet deficient in choline when fed to rats for as few as 3 days resulted in liver DNA damage. The damage could be monitored as alkali-labile lesions using alkaline-sucrose gradients as well as alkaline elution technique. The DNA damage disappeared when the choline-deficient diet was replaced by a choline-supplemented diet suggesting the alkali-labile lesions were repairable. The DNA damage was detected at a time when no liver cell death was detectable. The induction of DNA damage in a proliferating liver by the choline-deficient diet may be an early important event leading to initiation of liver carcinogenesis.

Animals↗