Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parenchymal hepatocytes isolated from adult rats were cultured on three types of collagen-containing substrata: collagen-coated plates, collagen membranes and confluent diploid human fibroblasts. Hepatocytes on the latter two substrata maintained characteristic morphology for at least 10 days in culture, whereas degenerative changes (cell death and formation of multinucleated hepatocytes) and growth of nonparenchymal elements were seen after 5 days in cultures on collagen-coated plates. Parallel findings were seen on basal and induced levels of cytochrome P-450 and NADPH-cytochrome C reductase. The basal levels of cytochrome P-450 were not measurable after day 3 in hepatocytes cultured on collagen-coated plates, whereas measurable levels were maintained in the hepatocytes cultured on the other two substrata. Addition of phenobarbital or methylcholanthrene at day 5 in culture caused an increase in cytochromes P-450 and P-448, respectively, only in hepatocytes cultured on collagen membranes and confluent fibroblasts. Analogous results were seen for the enzyme NADPH-cytochrome C reductase. The similarities in performance between hepatocytes on collagen membranes and on human fibroblasts show that a continuous collagen-containing substratum is important for optimal performance of hepatocytes in primary culture. The possible importance of cultures of hepatocytes on human fibroblasts for carcinogenesis studies is discussed.
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PMID:Primary cultures of hepatocytes on human fibroblasts. 11 6

Male Wistar rats were given repeated injections of sterigmatocystin (stg) and related compounds into the peritoneal cavity once a week for 23 weeks. Only stg alone produced mesothelioma in 20 of 40 rats given a total dose of 20 approximately 25 mg, while no mesotheliomas were found in rats injected O-acetyl-stg (AcO-stg) and dihydro-stg. There were two histological types in the mesothelioma induced by stg; the epithelioid and mesenchymal types. There was little loose connective tissue between the epithelioid cell tumors, whereas abundant dense collagen fibers were found between the cell nests of the mesenchymal cell types of mesothelioma. The hepatocellular carcinomas were found in a rat treated with stg and in five animals given AcO-stg. The fact that mesotheliomas could be induced in high incidence by direct intraperitoneal application of stg suggests a potent carcinogenicity of stg. Although both dihydro-stg and stg formed fine needle-like crystals when injected into the peritoneal cavity, dihydro-stg could not produce any mesothelioma. Dihydro-stg, reduction product of stg, has no double bond in the terminal furan ring. Therefore, the carcinogenicity of stg may be related more closely with the presence of a double bond in the terminal furan ring of stg than the physical form in the peritoneal cavity. AcO-stg may easily be absorbed from the peritoneum, so that it could not persist in the peritoneium for sufficient duration for carcinogenesis.
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PMID:Mesotheliomas induced by sterigmatocystin in Wistar rats. 21 76

The ultrastructure of primary hepatocytes cultured for 2 to 17 days on floating collagen membrane was evaluated. A pellet of the hepatic cell suspension used to inoculate the collagen membranes contained some single cells and many aggregates of two, three, or four cells. Desmosomes were split during the perfusion, but tight junctions and gap junctions remained intact. By 2 days in culture, the hepatocytes had formed a monolayer of cells of polygonal shape with newly synthesized desmosomes between cells. Since the flexible floating collagen membrane decreases in size as the monolayer forms, the hepatocytes do not flatten out, as is characteristic of cells cultured on a rigid substrate. Hepatocytes in culture for 10 days or less exhibited large lamellar arrays of rough endoplasmic reticulum, well developed Golgi complexes, and structures resembling bile canaliculi, which possess tight junctions and desmosomes separating them from the intercellular space. Microfilaments oriented parallel to the plasma membranes of adjoining cells and in an intermeshed network at the edge of the monolayer and beneath the plasma membrane bordering the medium increased in size and number in older cultures. After 17 days in culture, the cells maintained tight junctions, desmosomes, Golgi complexes, and rough endoplasmic reticulum in small lamellar stacks and in small vesicles. Since hepatocytes on the floating collagen membrane retain most of the subcellular structural elements characteristic of normally functioning hepatocytes for 2.5 weeks, this system may be valuable for future experiments involving drug metabolism and carcinogenesis in vitro.
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PMID:Ultrastructure of adult rat hepatocytes cultured on floating collagen membranes. 56 78

O6-Alkylguanine--DNA alkyltransferase (AGT) is a protein which removes the promutagenic O6-alkylguanine lesion induced in DNA by alkylating agents. Our results demonstrate that freshly isolated organoids from reduction mammoplasty specimens contain significant levels of AGT activity. AGT activity in breast epithelial cells shows interindividual variation. Constitutive levels of AGT activity remain unchanged during short-term serum-free culture of breast epithelial cells inside three-dimensional rat-tail collagen gel matrix. In the present study, we optimized conditions for depleting AGT activity in human breast epithelial cells cultured in three-dimensional collagen gel matrix using O6-methylguanine and O6-benzylguanine which are substrates for AGT. AGT activity was efficiently inactivated by exposure of cells to O6-methylguanine or O6-benzylguanine. Inactivation with O6-benzylguanine was more rapid, of greater magnitude and consistency and occurred at lower concentrations than with O6-methylguanine. Near-complete inactivation (> 99.5%) of AGT activity was reproducibly achieved with 50 microM O6-benzylguanine. In contrast, 500 microM O6-methylguanine was needed to obtain a maximal effect and this reduced AGT activity by only 53-93% of control. Within 30 min of adding the free base, 50 microM O6-benzylguanine depleted 95% of the levels of AGT compared to 30% inhibition with 500 microM O6-methylguanine. The profile for restoration of AGT activity was different following a 24 h incubation and subsequent removal of each of the guanine derivatives. AGT activity levels remained undetectable for at least 2 days after removal of 50 microM O6-benzylguanine from the medium and recovered to only 53% of control values after an additional 3 days. AGT activity levels remained undetectable for at least 2 days after removal of 50 microM O6-benzylguanine from the medium and recovered to only 53% of control values after an additional 3 days. In contrast, following removal of 500 microM O6-methylguanine, the activity was restored from its nadir of 16% of control values reaching pretreatment levels after 5 days. These results suggest that treatment with O6-benzylguanine may be used to modulate the incidence of transforming mutations in cultured human breast epithelial cells treated with chemical carcinogens which give rise to O6-alkylguanine adducts.
Carcinogenesis 1992 Oct
PMID:Depletion of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine in three-dimensional collagen cultures of normal human breast epithelial cells. 142 33

In this work the resistance of peroxisome-proliferated hepatocytes to hydrogen peroxide (H2O2) has been studied. The question has been raised as to whether this resistance is a response to cytotoxicity. In an initial series of experiments, hepatocytes were isolated from rats that had been treated with nafenopin (NAF-hepatocytes). Isolated cells were exposed to a H2O2-generating system or to H2O2 in pulses. The ability to attach to collagen was used as a toxicological endpoint. Loss of attachment was found to be correlated to glutathione (GSH) depletion, and NAF-hepatocytes were more resistant to GSH depletion and to loss of attachment induced by H2O2 than were control hepatocytes. NAF-hepatocytes were not resistant to hydroquinone or to adriamycin. It was also indicated that this resistance was related to an altered metabolism of H2O2, less dependent on GSH. In a second series of experiments, hepatocytes from altered hepatic foci-bearing rats, treated with nafenopin or di(2-ethylhexyl)phthalate (DEHP), were used. This model was used in an attempt to monitor the development of resistance in different subpopulations of hepatocytes. It was found that the majority of hepatocytes developed resistance towards H2O2, and that, for example, foci marker-positive hepatocytes were as resistant as marker-negative cells. In control experiments with this model, it was found that marker-positive cells were more resistant towards diethyl maleate (DEM) or phorone than were marker-negative cells. In addition to demonstrating the validity of the model, these control experiments indicate an increased steady-state level of H2O2 in cells from peroxisome proliferator-treated rats. Other control experiments suggested that a low GSH-peroxidase activity protected from, rather than aggravated, the effect of peroxisome proliferation on marker-negative and GSH-depleted cells. It is concluded that H2O2 metabolism may affect the function of collagen receptors, but that a shift in H2O2 metabolism, so that it becomes less dependent on GSH, conferred resistance to this effect. The apparent non-focal induction of resistance to peroxisome proliferators, as opposed to the focal induction of resistance induced by most liver carcinogens, may explain the lack of development of gamma-glutamyltranspeptidase-positive foci in peroxisome proliferator-treated rats.
Carcinogenesis 1992 Oct
PMID:Peroxisome proliferation and resistance to hydrogen peroxide in rat hepatocytes: is development of resistance an adaptation to cytotoxicity? 142 34

Molecules of the cadherin and integrin families involved in cell-cell and cell-matrix adhesion have been implicated in epithelial differentiation, carcinogenesis and metastasis. Having observed that a colon cancer cell line bound avidly to collagen type I, inducing integrin-triggered glandular differentiation, we investigated the regulation of integrin function in these cells. We modified a mammalian expression cloning system that used monoclonal antibody selection to clone cell surface molecules. Using attachment to collagen type I to select for adhesive phenotype, we isolated a complementary DNA clone that increases cell adhesion to components of the extracellular matrix. The corresponding gene (cell adhesion regulator, CAR) is located on the long arm of chromosome 16 (16q) and encodes a protein of 142 amino acids, which has an N-terminal myristoylation motif and a consensus tyrosine-kinase phosphorylation site at the C terminus. Removal of this tyrosine residue abolishes enhancement of cell-matrix adhesion. This gene may encode an adhesion signal transduction molecule that functions in the suppression of tumour invasion.
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PMID:Cloning and characterization of a gene that regulates cell adhesion. 842 14

'Ageing is a multistep, multifaceted, time-dependent phenomenon characterized by the decreased ability of a system to respond to exogenous and endogenous stress from either physical, chemical or biologic agents'. Cutaneous ageing provides a visible model of the interaction between endogenous (intrinsic) factors and exogenous (extrinsic) factors. In skin, the principal extrinsic-factor is ultraviolet light (UV) which is responsible for the constellation of changes termed photoageing. In recent years, much interest has been directed towards defining the ageing processes in skin and excellent comprehensive reviews have been compiled. This review aims to highlight several areas of developing knowledge, and focuses on the potential importance of environmental changes as they influence skin ageing and carcinogenesis. Repeated reference to the effects of UV on the skin are inevitable in any review of skin ageing and this is scarcely surprising as the skin contains many cells as well as subcellular and extracellular chromophores which are capable of absorbing energy within the UV spectrum. Cellular chromophores include among others keratinocytes, melanocytes, Langerhans cells, dermal fibroblasts and mast cells. Subcellular chromophores include keratin, melanin, collagen, elastin and a number of proteins, lipids and steroids (such as vitamin D). Urocanic acid, a photoisomerization product of the amino-acid histidine, may provide some limited photoprotection and some believe it to be important in UV induced immunosuppression. Understanding events at the molecular and biochemical level has unfortunately not been paralleled by clinical advances and the common, troublesome skin-problems of old age such as cancer, xerosis and pruritus remain a major cause of morbidity and yet are poorly explained.
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PMID:Aspects of cutaneous ageing. 179 84

Chronic ultraviolet (UV) irradiation is known to cause a variety of changes in the skin, including wrinkles, pigmented spots and carcinogenesis. To explore time dependent changes in several parameters with chronic UV irradiation, we examined the molecular changes in connective tissue, intracellular defence enzymes and free radical antioxidant substances in hairless mice skin caused by chronic exposure to UV-A including 2% UV-B. Connective tissue changes were estimated using hydroxyproline and isodesmosine assays as a measure of collagen and elastin concentrations, respectively. After 6 weeks irradiation, the insoluble collagen and elastin were both substantially elevated, as were the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). Continued UV irradiation resulted in a steady decline in SOD and lipid soluble antioxidants, while the GSH-Px remained elevated, suggesting that SOD and lipid soluble antioxidants in the skin may be involved in protecting it from UV damage and deteriorate with chronic irradiation.
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PMID:Effects of chronic exposure ultraviolet-A including 2% ultraviolet-B on free radical reduction systems in hairless mice. 179 51

The aim of this study has been to define cytotoxic mechanisms that may cause clonal expansion in the liver of pre-carcinogenic cells. An in vitro model, which has been described previously, was used. Hepatocytes were isolated from carcinogen-treated rats and a high proportion of the cells were gamma-glutamyltranspeptidase (GGT)-positive. The cells were incubated in suspension and exposed to toxic agents in concentrations that induced a moderate increase in cellular leakage within 3 h. Samples were withdrawn and sampled cells were then allowed to attach to collagen-coated plates. Attached cells were stained and the ratio of GGT-positive/GGT-negative cells (GGT-ratio) was determined. The initial GGT-ratio was 10.4 +/- 4.7% and an increased ratio was taken as a sign of toxicity that resulted in a selection of GGT-positive cells. In a first series of experiments it was shown that hydroquinone and menadione increase the GGT-ratio, while diquat, sodium selenite, diethyl maleate or phorone do not. However, diethyl maleate in combination with diquat increased the GGT-ratio. Hydrogen peroxide (5 mM) increased the GGT-ratio as effectively as hydroquinone (0.3 mM). Lower concentrations of H2O2 (0.05 mM) increased the GGT-ratio in GSH-depleted cells. The changes induced by hydroquinone and H2O2 in low concentration were reversible. In another series of experiments, plates coated with antibodies against beta 1-integrin were used. An increase in the GGT-ratio was obtained with anti beta 1-integrin, but not with broad spectrum anti-rat hepatocyte or anti-rat beta 2-microglobulin antibodies as substrata. These data suggested an involvement of the beta 1-integrin in the selection. Taken together, these data indicate that GGT-positive hepatocytes are protected against GSH depletion and oxidative stress that may result in reversible receptor alterations.
Carcinogenesis 1990 Jan
PMID:gamma-Glutamyltranspeptidase-positive rat hepatocytes are protected from GSH depletion, oxidative stress and reversible alterations of collagen receptors. 196 30

To determine whether the c-Ha-ras oncogene plays a role in the initiation of mammary carcinogenesis, an immortalized human breast epithelial cell line, MCF-10A, was transfected with the plasmid vector pHo6T1 containing the T24 Ha-ras oncogene and the aminoglycoside phosphotransferase gene, which confers resistance to geneticin. Transfected cells exhibited an altered pattern of growth and tridimensional morphology in collagen gel. They also exhibited anchorage-independent growth and loss of requirement for hormones and epidermal growth factor; in addition, they expressed invasiveness and increased collagenolytic activity in an in vitro system and became tumorigenic in irradiated nude mice, all properties indicative of malignant transformation. Transformed cells contained the mutated c-Ha-ras oncogene and expressed the p21 mutated protein. These data indicate that the c-Ha-ras oncogene is capable of inducing malignant phenotypes in immortalized human breast epithelial cells.
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PMID:Transformation of human breast epithelial cells by c-Ha-ras oncogene. 200 32


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