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Biomedical subjects

E Farber

Publications and source records attributed to E Farber.

At least 145 records · Page 8Linked to original sources
PubMed1980

Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens.

The induction of resistant hepatocytes in vivo in the rat has been observed with 21 different chemical carcinogens. The resistance was measured by the ability of the cells to proliferate as focal lesions in the presence of an environment that inhibits the original or surrounding hepatocytes from proliferation. This was created by a dietary 2-acetylaminofluorene plus a stimulus for cell proliferation, a single necrogenic dose of CCl4. The foci were readily visualized by staining for gamma-glutamyl transpeptidase activity. With most of the chemicals, a single administration at an appropriate time after partial hepatectomy is efficacious. However, with safrole and dieldrin, three doses over a 36-hr period were required to induce a significant number of foci of resistant hepatocytes. The presumptive preneoplastic nature of the resistant hepatocytes and the possible usefulness of this approach for the development of a new in vivo short-term test system for carcinogens are discussed.

2-Acetylaminofluorene↗
PubMed1980

Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis.

This study was undertaken to answer the following question. Is the phenotypic diversity that is characteristic of hepatocellular carcinomas acquired early during carcinogenesis, or is it more likely to be a property added late in the process? This question was posed using a new model for the sequential analysis of hepatocarcinogenesis. This model utilizes a single initiating dose of a carcinogen, such as diethylnitrosamine, followed by the selective stimulation of the rare, initiated hepatocyte to proliferate under conditions in which the proliferation of the majority of uninitiated hepatocytes is inhibited. Under these conditions, discrete early foci of altered hepatocytes and hyperplastic foci and nodules are quite well synchronized for about 10 to 12 cell cycles, after which the synchrony is progressively lost. As phenotypic expressions, cell proliferation, judged by radioautography after the administration of [3H]thymidine and the activities of four enzyme markers, two positive ones, gamma-glutamyltranspeptidase and DT-diaphorase, and two negative ones, glucose-6-phosphatase and adenosine triphosphatase, all judged histochemically, were used. At the earliest time of observation, 7 days, and at subsequent time points thereafter, all histologically recognizable foci and nodules showed variable degrees of staining for each enzyme activity. Prior to selection, gamma-glutamyltranspeptidase activity was much more consistent than was that of the others; however, during and after the selection, the four markers showed almost the same consistency among developing lesions. During the period of selection, between 80 and 90% of hepatocytes in the proliferating nodules were labeled with [3H]thymidine, while only an occasional labeled hepatocyte was seen in the foci prior to selection and in the nodules following selection. In the postselection period, the majority of nodules acquired the histochemical and architectural properties of normal liver, while a minority persisted as typical hyperplastic nodules. This study suggests that phenotypes of carcinogen-altered hepatocytes are variable, but whether the histochemical diversity among the lesions is merely due to environmental variation or is a reflection of a more basic genotypic variability remains a fundamental question.

Animals↗
PubMed1980

The sequential analysis of liver cell necrosis: inhibition of diethylnitrosamine- and dimethylnitrosamine-induced acute liver cell death by posttreatment with diethyldithiocarbamate.

Posttreatment with diethyldithiocarbamate (DEDTC) largely prevented the development of acute hepatocellular necrosis induced by diethylnitrosamine (DEN) and dimethylnitrosamine (DMN) in male Fischer rats as monitored by the release of glutamate-pyruvate transaminase and sorbitol dehydrogenase into the serum and by histologic examination. Liver cell necrosis was evident with a dose of 25 mg of DEN/kg and was progressive with increasing doses of DEN. DEDTC (50 mg/kg; three times at 4-hour intervals) was given at 4 or 8 hours after the administration of DEN (100 mg/kg), time points at which at least 50% and 75%, respectively, of the administered DEN had disappeared from both the serum and liver. Under these conditions, DEDTC prevented liver cell necrosis, except for a few isolated cells. Similar inhibition was also observed when DEDTC was given 4 hours after the administration of a necrogenic dose of DMN (20 mg/kg). DEDTC, when administered 4 hours after DEN, delayed the rate of clearance of DEN and of ethylation of DNA and RNA but did not significantly affect the total extent of ethylation of rat liver nucleic acids. These results offer further support for the multistep hypothesis for the development of liver cell necrosis.

Animals↗
PubMed1980

The genesis of cancer with chemicals.

In studying the sequence of events during the induction of cancer with chemicals, major emphasis in recent years has been given to the identification of possible carcinogens and to their metabolism and interactions with cellular constituents, such as DNA, in target cells. The repair of relevant chemical lesions seems to be important, and special emphasis can be given to the cellular aspects of chemical carcinogenesis, the biological nature of the initiated cells, and the basis for their growth into focal proliferations during promotion. A new model for the sequential analysis of steps during the earlier periods in cancer development in the liver with chemicals has been developed, delineating the probable role of cell injury as a rate-limiting step in cancer development in organs that are quiescent with respect to cell proliferation, and the possible beneficial role of the early events in chemical carcinogenesis in natural selection.

Animals↗
PubMed1980

Persistence of resistant putative preneoplastic hepatocytes induced by N-nitrosodiethylamine or N-methyl-N-nitrosourea.

The administration of either N-nitrosodiethylamine (diethyl-nitrosamine) to intact male F-344 rats or N-methyl-N-nitrosourea to similar animals 18 hr after partial hepatectomy results in the induction of altered resistant hepatocytes that persist for up to 36 weeks with no perceptible decrease in their number. The criterion for resistance was the ability to proliferate rapidly and to develop into foci or nodules when exposed to a level of dietary 2-acetylaminofluorene that inhibits the proliferation of the vast majority of hepatocytes when liver cell proliferation is stimulated by surgical or chemical partial hepatectomy. Since this selection procedure, when coupled with a single dose of diethylnitrosamine, is associated with a high incidence of liver cancer as compared to appropriate controls, and since similar foci and nodules were shown previously to be one site of origin for hepatocellular carcinoma in this model, the induction of resistant hepatocytes is interpreted as initiation. Thus, these results suggest that initiation of liver carcinogenesis in this model is irreversible, at least for a period of 36 weeks.

2-Acetylaminofluorene↗
PubMed1980

Purification and partial characterization of a preneoplastic antigen in liver carcinogenesis.

A preneoplastic antigen has been isolated from the microsomal fraction of the hyperplastic nodules of rat liver. During the purification, the presence of preneoplastic antigen was monitored by microcomplement fixation test and double immunodiffusion plate following reaction with antiserum specific for this antigen. The antigen was purified by seven steps with a purification factor of 167 and 11% yield. It migrated as a single protein band, both in nondenaturing and denaturing polyacrylamide gel electrophoresis; showed a single sharp peak in an isoelectric focusing column at pH 4.75; and had a single serine amino-terminal amino acid. In the absence of detergent during purification, this protein tends to form molecular aggregates. It appears to be a glycoprotein based on the positive periodic acid-Schiff stain and absorption by concanavalin A:Sepharose affinity column chromatography. Amino acid analysis indicated that the protein is acidic, having acidic amino acids (aspartate and glutamate) and basic amino acids (lysine, arginine, and histidine) in a ratio of 6.8. An estimate of the molecular weight by gel filtration gave a value of 145,000 and a calculated Stokes radius of 41.5 A. Electrophoresis under denaturing conditions on sodium dodecyl sulfate-polyacrylamide gel indicated that this protein is a dimer consisting of two subunits of equal molecular weight (M.W. 74,000). Circular dichroism spectra indicated alpha-helix contents at 298 and 222 nm of 25.5 and 28.3%, respectively. A similar protein is present in the endoplasmic reticulum of normal rat liver, but in a much lower concentration.

Amino Acids↗
PubMed1980

Reversible and irreversible lesions in processes of cancer development.

Most known carcinogenic processes consist of a multistep sequence in which new cell populations are the links in the chain of events triggered by the chemical carcinogen. Although the later steps are self-generating, in that they require no obvious external stimulus, the early steps are very much environment-dependent. Initiation of chemical carcinogenesis appears to consist of at least two steps, a reversible biochemical one and a round of cell proliferation which results in the generation of a relatively permanent, irreversible rare event, the promotion of initiated cells. The selection of these cells - promotion - is largely reversible, with only an occasional selected focal area of proliferation persisting to the next step, again a rare event. The selections of this and subsequent rare events are largely unknown as to their reversibility. The need to delineate each step is emphasized.

Animals↗
PubMed1979

Multiplicity of induction patterns of rat liver microsomal mono-oxygenases and other polypeptides produced by administration of various xenobiotics.

Induction of hepatic microsomal mono-oxygenase species after administration of various xenobiotics is a well-documented phenomenon. To examine the number and specific species of rat liver microsomal membrane polypeptides involved in such responses, we have used sodium dodecyl sulphate/polyacrylamide-gel electrophoresis to analyse microsomal fractions from animals treated with a number of important xenobiotics. The following are the principal points to have emerged from this study. 1. A minimum of twelve electrophoretically distinct patterns of induction of haemopolypeptides and other polypeptides could be distinguished after administration, either singly or in certain combinations, of phenobarbital, 3-methylcholanthrene, polychlorinated biphenyls, 2-acetylaminofluorene, safrole (or isosafrole), pregnenolone-16 alpha-carbonitrile and ethanol. The patterns consisted of various permutations of the amounts of eight polypeptides of 47000-56000 mol.wt., of which at least three were haemopolypeptides. The possible identities of these polypeptides, which included species of cytochrome P-450, cytochrome P-448 and epoxide hydratase, are discussed. 2. Agents (3-methylcholanthrene, benzo[a]-pyrene, polychlorinated biphenyls, 2,3,7,8-tetrachlorodibenzo-p-dioxin and beta-naphthoflavone) that result in the induction of cytochrome P-448 caused a marked increase in two polypeptides of 54000 and 56000 mol.wt., whereas safrole and isosafrole induced only the former polypeptide. 3. Administration of 2-acetylaminofluorene resulted in the induction of two polypeptides; evidence is presented that suggests that one of these is a species of epoxide hydratase [cf. Levin, Lu, Thomas, Ryan, Kizer & Griffin (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 3240-3243] ANd that the other may be a novel haemopolypeptide. 4. The overall results emphasize the complexity of the responses exhibited by rat liver microsomal fractions to the administration of xenobiotics.

2-Acetylaminofluorene↗
PubMed1979

Sequential analysis of hepatic carcinogenesis: the comparative architecture of preneoplastic, malignant, prenatal, postnatal and regenerating liver.

The organizational pattern of hepatocytes in hyperplastic nodules, probable precursors of hepatocellular carcinoma, was examined sequentially at different stages in the carcinogenic process, and compared with the patterns in hepatocellular carcinomas, in developing liver and in regnerating liver. Scanning as well as transmission electron microscopy, and histochemistry with light microscopy were used. The hepatocytes in the hyperplastic lesions were arranged in plates 2 or more cells thick and glands, in contrast to the one-cell-thick plates of hepatocytes in normal mature liver, and showed unusualy separation from eachother, with irregularly dilated bile canaliculi. The organizational pattern found in the hyperplastic lesions shared properties with developing liver in the perinatal period, regenerating liver following the peak of cell division, and some hepatocellular carcinomas. Unlike the normal, in which there is a highly predictable time scale for change, an apparent delay or interruption of maturation may be of importance in lesions that persist and ultimately evolve into hepatocullular carcinoma.

Animals↗
PubMed1979

Sequential analysis of hepatic carcinogenesis: a comparative study of the ultrastructure of preneoplastic, malignant, prenatal, postnatal, and regenerating liver.

The objective of this study was to compare the fine structure of presumptive preneoplastic hepatocytes at various times during liver carcinogenesis with that of normal, developing, and regenerating liver and of hepatocellular carcinomas, using transmission and scanning electron microscopy. A new model of liver carcinogenesis was used in which several of the early steps are quite well synchronized. A single initiating dose of diethylnitrosamine induced isolated islands of altered hepatocytes. The cells were characterized by persistence of glycogen despite starvation, increase in smooth endoplasmic reticulum, and hypertrophic nucleoli. Following intense selection of the altered hepatocytes by dietary 2-acetylaminofluorene plus partial hepatectomy, the affected hepatocytes proliferated rapidly to produce basophilic foci. These early hyperplastic lesions revealed stellate-shaped dilated bile canaliculi lined by blebs and abnormally thick elongated microvilli, a decreased number of microvilli on the sinusoidal surface, a marked increase in smooth endoplasmic reticulum, large nucleoli, and bundles of pericanalicular microfilaments. A majority of the proliferating lesions reacquired a normal organizational pattern within several weeks after partial hepatectomy and could not be distinguished from normal liver. A small number continued to grow and become typical persistent hyperplastic nodules. These showed significant widening of intercellular spaces between hepatocytes, elongated microvilli over large regions of the cell surface, many invaginations of the cell membrane, and irregularly shaped bile canaliculi. Sequential changes in focal hyperplastic hepatocytes during carcinogenesis could be distinguished from normal, developing, and regenerating liver. The major differences involved the cell surfaces and cytoplasmic organelles. The findings are compatible with the hypothesis that a carcinogen may act by inducing alterations in a small number of hepatocytes and that hepatocellular carcinomas arise through stepwise evolutional changes in these cells.

Animals↗
PubMed1979

Induction of hepatic neoplastic lesions in mice with a single dose of hycanthone methanesulfonate after partial hepatectomy.

Experiments were designed to determine whether hycanthone methanesulfonate (1-([2-(diethylamino)ethyl]amino)-4-(hydroxymethyl)thioxanthen-9-one monomethanesulfonate), an antischistosomal drug, and its analog, IA-4-N-oxide (8-chloro-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazole 5-methanol monomethanesulfonate), will induce neoplastic lesions in the livers of mice not infected with Schistosoma mansoni. All the mice received a single i.m. injection of hycanthone methanesulfonate (76 mg/kg), IA-4-N-oxide (80 mg/kg), or an equivalent volume of the solvent, 0.9% NaCl solution, 42 hr after partial hepatectomy. Of the mice receiving hycanthone methanesulfonate and living 200 days or longer, hepatocellular carcinoma was seen in 11.5% and liver sarcoma was seen in 4.2%. This type of malignant neoplasm was not seen in the animals receiving either IA-4-N-oxide or 0.9% NaCl solution. In addition, mice receiving hycanthone methanesulfonate showed a significantly higher incidence of both type 1 (43% compared to 21% in controls) and type 2 (21% compared to 12% in controls) hepatocyte neoplasms. Mice receiving IA-4-N-oxide showed no increased incidence of neoplasms.

Animals↗
PubMed1979

Persistence of DNA damage during development of liver angiosarcoma in rats fed dimethylnitrosamine.

Chronic feeding of a diet containing dimethylnitrosamine (50 ppm) to rats resulted in liver DNA damage monitored as slow sedimentation of the DNA compared to that of the control in alkaline sucrose gradients. The damage in rat liver DNA could be seen within 2 days after beginning the feeding of diets containing the carcinogen and was progressive with the time of feeding, up to 8 weeks. Extended feeding up to 15 or 31 weeks did not result in a proportionate increase in the damage to the DNA. The DNA damage observed at 8 weeks persisted until 31 weeks, at which time liver angiosarcoma was present. Despite the fact that the DNA damage induced by dimethylnitrosamine appears to involve the bulk of the liver DNA, the tumors developed were entirely from vascular endothelium. The implication of these results in the initiation of carcinogenesis is discussed.

Animals↗