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Biomedical subjects

E Farber

Publications and source records attributed to E Farber.

At least 19 recordsLinked to original sources
PubMed2000

The resistance phenotype in the development and treatment of cancer.

Phenotypic resistance, acquired early in carcinogenesis, has an established role in the pathogenesis of cancer in well-characterised experimental systems, and possibly also has a role in the origin of human cancer. It has been suggested that sunlight, an established risk factor for human skin carcinogenesis, is able to induce rare altered cells resistant to toxicity and to favour their clonal expansion via toxic effects exerted on normal keratinocytes. Other major risk factors for human neoplasia, including smoking and ageing, may also act partly through imposition of a constrained growth environment in the target organ to favour the emergence of altered resistant cells. Strategies aimed at counteracting this constrained environment could be effective in attenuating the force that sustains clonal expansion of altered cells.

Animals↗
PubMed2000

Risk assessment for possible carcinogens: a critical look.

Our overall understanding of mechanisms of toxicology in relation to human disease, with prevention of disease as a major objective, depends in part on the development of an adequate number of ways to assess risks, both short term and long term. Despite the cost, the long duration of the test, and some pitfalls, the long-term animal tests remain, to date, the only reliable assay for possible carcinogens. Recent work has concentrated increasingly on the development of short-term tests to replace the long-term tests. Such a development would be most welcome from several points of view. To date, a variety of approaches have been or are being used. These include (1) activation to an alkylating agent with DNA as the most important target, generating possible mutations in DNA and DNA damage with or without repair, (2) induction of cell proliferation, at least a few cycles, with DNA synthesis as the major target, again favoring mutations, and (3) decrease in cell-to-cell communication (gap-junctional intercellular communication) as a supposed test for promotion. None of these proposed assays are reliable indices for possible carcinogenic effects of chemicals or other agents; the scientific basis for this negative conclusion is discussed.

Carcinogenicity Tests↗
PubMed1999

The slow induction of resistant hepatocytes during initiation of hepatocarcinogenesis by the nongenotoxic carcinogen clofibrate.

This study was designed to explore whether a well-known nongenotoxic liver carcinogen, clofibrate, would induce rare resistant hepatocytes similar to those seen during initiation of hepatocarcinogenesis with many genotoxic carcinogens. Male young adult F344 rats were exposed to a control diet containing 0.5% (w/w) clofibrate for 3, 6, or 10 months. After 1 month on a diet free of clofibrate, the animals were assayed for resistant hepatocytes by a standardized selection procedure using 2-acetylaminofluorene as the inhibitor and partial hepatectomy as a strong stimulus for cell proliferation. No resistant hepatocytes were found in the animals exposed to clofibrate for 3 months or in any of a series of control animals. However, animals on the clofibrate for 6 and 10 months contained resistant hepatocytes that were clonally expanded to produce hepatocyte nodules. These nodules were indistinguishable on gross and microscopic examination from hepatocyte nodules seen in animals in which nodules are induced with one of many different genotoxic carcinogens. Also, like those nodules, the nodules seen in the animals exposed to clofibrate stained positively for glutathione S-transferase 1-1 and gamma-glutamyl transpeptidase and negatively for ATPase. The evidence from this study indicates that the nongenotoxic carcinogen, clofibrate, induces early cellular changes in the liver that are very similar to those induced by many different genotoxic carcinogens. These changes are manifest as a resistance phenotype in a few scattered hepatocytes that now can be clonally expanded selectively to form hepatocyte nodules. However, the resistant hepatocytes are induced by clofibrate much more slowly. Whether this basic similarity pertains to the later steps in the hepatocarcinogenic process remains to be studied.

2-Acetylaminofluorene↗
PubMed1999

A critical perspective in cancer research (Review).

Over the past few decades, there has been a tremendous increase in cancer biology data and treatment. Cancer research has opened exciting new areas of cellular and molecular biology. Month by month, new genes which regulate the carcinogenesis process are being discovered. The result is an incredible knowledge of cancer: what makes a cancer cell a cancer cell, what cancer cells need to develop, and how cancer cells behave, interact, overgrow and die. In parallel, gene manipulation within cells lets us foresee future possibilities of new cancer treatments. On the other hand, this combination of increased knowledge and powerful new techniques has provided no effective cancer therapy. As it has been quoted during the meeting held in New York, August 1999: <. The success in treating Hodgkin's disease means that patients now live enough to develop complications related to the treatment>. Thus, after dedicated decades of excellent research, cancer remains a significant human, clinical, and economical burden. The purpose of this review is 2-fold. First, to analyze areas of basic cancer research that still await adequate scientific explanations. Second, to stress that, for its continuing advancement, cancer research is dependent upon close relationships among many disciplines; an intimate alignment of oncologists with biochemists, geneticists, immunologists, experimental pathologists, and pharmacologists is needed. In light of the great success registered at the basic science level but lack of effective therapies, it would be wise to establish human and economical resources addressed to a multidisciplinary collaborative effort in cancer research.

Humans↗
PubMed1997

Chordoma: a case report.

BACKGROUND: Chordomas are tumors of notochordal origin that account for approximately 1%-4% of all primary malignant bone tumors. The majority of patients with chordomas have a poor surgical prognosis due to extent of disease at diagnosis. These lesions have been previously classified based solely on their location. METHODS: We describe here a case report of a posterior epidural C5-T1 chordoma that was discovered in a young patient who presented with weakness and paresthesia in all four extremities. This lesion was notable for its extraosseous and extradural characteristics. RESULTS: C5-T1 laminectomy with gross total resection of the mass led to complete resolution of all symptoms. There has been no evidence of tumor recurrence to date. CONCLUSIONS: We propose here a new classification system for chordomas that emphasizes the difference in resectability of these lesions depending on the space they occupy and the presence or absence of an osseous connection.

Adolescent↗
PubMed1997

Changes in drug-metabolizing enzymes of rats in ciprofibrate-induced hepatic nodules.

1. Premalignant rat liver nodules produced in the resistant hepatocyte model, by exposure to carcinogenic chemicals (diethyl nitrosamine and 2-acetamidofluorene), and partial hepatectomy, exhibit decreased xenobiotic hydroxylase activities and increased conjugase activities, which are considered responsible for increased resistance to xenobiotic toxicity. 2. However, premalignant rat liver nodules generated by feeding the hypolipidaemic, peroxisomal proliferating drug, ciprofibrate, in a hypolipidaemic model, exhibit decreased hydroxylase activities but decreased conjugase activities also. 3. It is considered that reactive oxygen species (ROS) are generated in both the resistant hepatocyte model and in the hypolipidaemic model, resulting in lipid peroxidation, loss of haem, cytochromes and hydroxylase activities. 4. However, whereas there is a rebounding compensation of conjugase enzymes in the resistant hepatocyte model, this does not occur with the hypolipidaemic model, as peroxidation is probably persistent and the conjugases are continuously destroyed.

2-Acetylaminofluorene↗
PubMed1996

Changes in tRNA pattern in ethionine-induced rat putative preneoplastic hepatocyte nodules.

As part of a study to explore further the biochemical pathology of chemical hepatocarcinogenesis, cytoplasmic tRNA patterns have been studied in ethionine-induced rat putative preneoplastic nodules in comparison to surrounding non-nodular liver and control liver. A new h.p.l.c. methodology, able to resolve contemporaneously the numerous components in a tRNA population, has been used. The results obtained indicate the presence of marked differences in the chromatographic profiles of hepatocyte nodules, non-nodular surrounding liver and control liver. The differences are both quantitative and qualitative, with some chromatographic peaks showing increases and some decreases or absences. Also, new peaks are seen reproducibly in the nodules. The data show major changes in the tRNA population during hepatocarcinogenesis that might have mechanistic implications.

Animals↗
PubMed1996

Alcohol and other chemicals in the development of hepatocellular carcinoma.

A positive association between the incidence of hepatocellular carcinoma and the consumption of alcoholic beverages has been reported from some countries. The possible mechanistic nature of the association remains unclear, however. The effects of alcohol, as ethanol and as ethanol in various complex mixtures in the many different alcoholic beverages, were compared with the effects of well-known genotoxic and nongenotoxic or epigenetic carcinogens in carcinogenesis. There is no convincing evidence that alcohol can initiate the long multistep process of development of hepatocellular carcinoma. Thus, it appears that alcohol cannot be considered as a complete carcinogen. The effects of alcohol were also compared with known promoting agents for liver cancer. Although the available data are less clear, nevertheless it appears that alcohol cannot be considered as a bona fide promoting agent for liver cancer development. The most likely roles of alcohol in the genesis of liver cancer are: (1) to induce a well-known precancerous liver lesion, cirrhosis, and (2) to modulate, in an as yet ill-defined manner, the process of cancer development with known human carcinogenic influences such as hepatitis due to hepatitis B and hepatitis C viruses. Alcohol is well known to induce several enzymes in the liver and, thus, could theoretically modulate one or more steps in the carcinogenic process. Because alcohol has been found to alter cell membranes in well-defined ways and cell membrane changes, especially in the liver endoplastic reticulum, appear to be common in the later steps in liver cancer development, it is suggested that one site of alcohol action might be in the modulation of the biophysical composition of the liver endoplasmic reticulum and plasma membrane, favoring the cellular evolution to neoplasia.

Animals↗
PubMed1995

Effects of peroxidative stress and age on the concentration of a deoxyguanosine-malondialdehyde adduct in rat DNA.

The effect of age and peroxidative stress on the concentration of a deoxyguanosine malondialdehyde adduct (dG-MDA) in rat tissues was investigated. Vitamin E deficiency had no effect on the dG-MDA content of liver DNA in rats fed a diet containing 10% corn oil. When 2% cod liver oil was added to this diet, the dG-MDA content of liver DNA doubled in the positive controls fed a high level of vitamin E (100 ppm dl-alpha-tocopherol), and there was a further increase when vitamin E was deleted. Neither iron nitrilotriacetate administration nor choline deficiency had any effect on the dG-MDA content of liver DNA. Carbon tetrachloride had a lowering effect. The failure of iron or carbon tetrachloride administration and of vitamin E deficiency to increase liver dG-MDA is consistent with their failure in previous experiments to affect the urinary excretion of dG-MDA. In contrast, these forms of peroxidative stress produce large increments in the urinary excretion of MDA adducts with lysine, reflecting increased formation and degradation of MDA-modified proteins. DNA appears to be protected from modification by MDA produced at extranuclear sites. The frequency of dG-MDA in different tissues of 4-month-old rats varied markedly: brain >> liver > kidneys and testes. Higher concentrations of dG-MDA were found in the liver and kidneys, but not the testes, of 25-month-old rats. The determinants of the concentration of dG-MDA in DNA merit further investigation.

Aging↗
PubMed1995

Liver biochemical pathology of choline deficiency and of methyl group deficiency: a new orientation and assessment.

New information on the pathologic effects of a choline deficient diet in the rat, in relation to the biochemical events, has led to a new understanding and orientation of the pathogenesis of both acute and chronic consequences in the liver. The biochemical pathology of choline deficiency is quite different than that of methyl group (lipotrope) deficiency. These studies in our laboratory and elsewhere are generating new insights and hypotheses concerning the genesis of hepatocyte necrosis and hepatocellular carcinoma in the rat fed a choline deficient diet.

Animals↗
PubMed1994

An origin of presumptive preneoplastic foci and nodules from hepatocytes in chemical carcinogenesis in rat liver.

The sites and times of appearance of preneoplastic foci in rat liver acinus during the first 11 days after initiation with diethylnitrosamine and promotion with 2-acetylaminofluorene plus partial hepatectomy was observed in three separate experiments. Foci appeared as alterations of hepatocytes followed by focal proliferation in each of the three zones before any ductular epithelial cell ('oval cell') proliferation. The dissociation between foci and 'oval cell proliferation' is strong evidence against a role of the latter in generating preneoplastic hepatocytes in hepatocellular carcinogenesis.

Animals↗
PubMed1994

Hypermethylation of replicating hepatic DNA following N-methyl-N-nitrosourea administration.

Changes in the degree of methylation of cytosine in DNA are considered to be mechanistically important in modulating gene expression. To gain a better understanding of the relationship(s) linking onco-proliferative processes and enzymatic DNA methylation, a study has been carried out on the hepatic DNA methylation pattern during DNA replication following partial hepatectomy (PH), mitogen treatment and N-methyl-N-nitrosourea (MNU) administration in rats. The following results were obtained: (i) DNA hypomethylation was seen during DNA synthesis, with each of the 3 stimuli, namely MNU administration, partial hepatectomy, and hepatomitogen treatment; (ii) the level of DNA hypomethylation was not quantificatively related to the extent of DNA replication as measured by incorporation of [3H]thymidine into hepatic DNA; (iii) MNU administration under conditions conducive to carcinogenic development, i.e. during the S phase of compensatory cell proliferation, caused hypermethylation of replicating hepatic DNA, as shown by HpaII and MspI restriction patterns.

Animals↗
PubMed1994

Multiple sites of control of glutathione S-transferase P1-1 in rat liver.

Glutathione transferase P1-1, normally very low in adult rat liver, is induced by a single intravenous dose of lead nitrate. In this transient induction, there are at least three sites of regulation or control. These are transcription, post-transcription, and post-translation. The increase in transcription is evident both by nuclear run-off analysis and by measurement of mRNA levels. The other two sites of control were seen in actinomycin D-treated animals in which RNA synthesis was inhibited by over 80%. Treatment with actinomycin D increases the stability of the mRNA and also somehow inhibits the conversion of a glutathione transferase protein to an enzymatically active form. These three sites offer possibilities for the study of mechanisms of control for this interesting enzyme that may play a role in chemical carcinogenesis and in drug resistance.

Animals↗