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)

Preneoplastic liver foci were produced in female Wistar rats by the administration of 2-acetylaminofluorene (0.03% w/w) in the diet for 174 days. Increased UDP-glucuronyltransferase (UDP-GT) could be visualized immunohistochemically in the same focal areas which were ATPase-negative and gamma-glutamyltranspeptidase-positive. Immunohistochemical detection was possible using rabbit anti-UDP-GT and peroxidase-labeled swine anti-rabbit immunoglobulins. The results of immunohistochemistry were substantiated by enzyme determination in microdissected material. UDP-GT activity was 5-fold higher in focal areas in comparison with the surrounding liver tissue. Increased UDP-GT activity in conjunction with the altered pattern of other drug-metabolizing enzymes is consistent with increased resistance of preneoplastic cells to the cytotoxicity of carcinogens. Immunohistochemical detection of UDP-GT may provide a new marker for preneoplastic lesions which, in conjunction with other markers, may prove useful in analyzing the various stages of liver carcinogenesis and the remodeling of preneoplastic lesions after cessation of carcinogenic stimuli.
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PMID:Immunohistochemical and biochemical detection of uridine-diphosphate-glucuronyltransferase (UDP-GT) activity in putative preneoplastic liver foci. 613 91

The roles of chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) in carcinogenicity of vinyl chloride (VC) have been studied by comparing biological effects of VC exposure with those of 2,2'-dichlorodiethylether (bis(chloroethyl)ether, BCEE) as a metabolic precursor of CAA. Biological end-points investigated were covalent protein binding, nucleic acid (RNA and DNA) alkylation and the potency of the two chemicals to induce preneoplastic ATPase-deficient foci in rat liver. After exposure of rats to [1-14C]BCEE, BCEE derived radioactivity was bound to liver proteins. Analysis of hydrolysates of liver RNA and DNA gave no indication for the formation of either 7-N-(2-oxoethyl)guanine, 1,N6-ethenoadenine or 3,N4-ethenocytosine residues within the nucleic acids. After application of VC, BCEE or chloroethanol [CE), also a precursor of CAA) to young rats, only animals exposed to VC developed preneoplastic hepatocellular ATPase-deficient foci. From these investigations it is concluded, that CEO (which is not formed during metabolism of BCEE and CE), not CAA, is the ultimate carcinogenic principle in VC carcinogenicity.
Carcinogenesis 1983 Nov
PMID:Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: comparative studies with 2,2'-dichlorodiethylether. 619 38

One, two, and three applications of DMBA in mineral oil to hamster buccal pouch mucosa did not result in obvious histologic alterations in experimental periods ranging from 4 1/2 hours to 2 weeks after the last DMBA application. However, there were significant increases in the number of Langerhans cells, as disclosed histochemically with ATPase staining. There was also an increase in the length and size of the dendritic processes of the Langerhans cells. Applications of DMBA in oil resulted in a consistently significant increase in Langerhans cells when compared to the buccal pouch mucosa of untreated animals. However, mineral oil applications also resulted in a slight increase in Langerhans cells when compared to the mucosa of untreated controls. The major effects of the DMBA on Langerhans cells occurred after 2 weeks and with increasing numbers of applications. The increase in Langerhans cells is interpreted as an enhanced response by immunologically competent cells which may represent an early immune response to the very early changes in carcinogenesis.
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PMID:Acute effect of DMBA application on Langerhans cells of the hamster buccal pouch mucosa. 620 76

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) influences neither the State 3 nor the State 4 respiration in rat liver mitochondria. The respiratory control and ADP/O ratio were also unaffected by TPA. The oligomycin-sensitive ATPase activity in submitochondrial particles remained unaltered upon TPA addition, whereas the NADH oxidase activity was slightly inhibited at a very high concentration of TPA (15% decrease at 17 microM TPA). The activity of the superoxide dismutase located to the mitochondria was insensitive to the tumor promoter, and no change in the rate of H2O2 production was found on TPA treatment in vitro. Thus, the mitochondrion is not a likely candidate for the site of action of the tumor promoter.
Carcinogenesis 1983
PMID:Oxygen uptake, ATPase activity, and superoxide dismutase activity in isolated rat liver mitochondria are not influenced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 622 26

Chronic exposure of rodents to high dose levels of drugs, food additives and environmental chemicals frequently results in liver enlargement. Several of these compounds have been found to enhance the incidence of liver tumors in animals briefly exposed previously to hepatocarcinogens. Accordingly, it has been advanced that these agents act as tumor promoters. This contention has remained subject of controversy following reports that these substances may also cause liver tumors in noncarcinogen-treated rodents, particularly in those characterized by a relatively high incidence of "spontaneous" liver tumors. Since many of these chemicals are in common use, a crucial question would seem to be whether such effects are due to facilitation of the expression of pre-existing oncogenic potential, i.e., to tumor promotion, or to the synergistic action of weakly carcinogenic agents. As a result of mechanistic differences tumor promotion and syn-carcinogenesis must exhibit different dose-time-response characteristics, and, accordingly, it should be possible, in principle, to discriminate between these phenomena. However, since tumor manifestation periods in low-dose groups frequently exceed the animals average lifespan, this approach may not always yield conclusive data, unless a sensitive early marker of carcinogenic activity can be employed. There is evidence that enzyme-deficient preneoplastic areas in liver can be used for this purpose. A strong quantitative correlation between carcinogen dose, the extent of ATPase deficient areas, and the subsequent appearance of tumors has now been established for a number of hepatocarcinogens. Experimental data are consistent with the concept that two critical events (hits) are required for induction of ATPase deficiency in hepatocytes. The first hit is carcinogen-dependent, whereas the second hit would seem to be due to time-dependent event(s). Tumor-promoters, such as phenobarbital, were found to accelerate and increase formation of preneoplastic islets. This evidence, together with data indicating that the compound is devoid of carcinogenic potential, suggests that phenobarbital may be operative at relatively early stages of hepatocarcinogenesis by increasing the probability of the occurrence of the time-dependent second hit. Such effects are dose-dependent and appear to be related to the induction of liver enlargement. The changes in hepatocellular ploidy status and atypical nuclear figures observed during phenobarbital treatment and cessation thereof, suggest that this compound might induce abnormal redistributions of genetic material. It is postulated that these cytological changes may result in phenotypical manifestation of recessive oncogenic information.
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PMID:Quantitative aspects of chemical carcinogenesis and tumor promotion in liver. 622 10

In the course of chemically induced liver carcinogenesis as one of the earliest changes, the histochemically demonstrable focal loss of nucleoside 5'-triphosphatase activities (ATPase) is detectable. The exact quantitation and differentiation of these alterations can be achieved by biochemical analysis in microdissected preneoplastic foci. The preparation of focal tissue was facilitated using a microscopic-microdissecting apparatus [1]. By microanalytic determination of hydrolytic cleavage of 32P from gamma 32P-ATP a decrease of total ATPase activity to about 70% was found. Furthermore, the alteration of ATPase activities in course of chemically induced liver carcinogenesis in rats will be described.
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PMID:Biochemical quantification of ATPase activities during liver carcinogenesis. 622 16

Cell cultures and in vitro oncogenic transformation offer a powerful tool for exploring conditions and compounds that may inhibit malignant transformation following exposure to environmental or therapeutic agents. We find, using rodent cell cultures, that retinoids inhibit radiation-induced transformation and eradicate the enhancing effect of tumor promotors. These protective effects of the retinoids are not mediated at a chromosomal level but are reflected at the cell membrane level via the membrane-associated transport enzyme Na/K-ATPase. Using these systems, we also find that hypothyroid condition is protective and that thyroid hormone T3 is essential for the induction of both radiation-induced and chemically induced carcinogenesis, and thus may also play a crucial role in cancer induction in vivo.
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PMID:Nutritional and hormonal factors in the prevention of carcinogen-induced neoplastic development in vitro. 629 59

The effects of metals on subcellular organelle functions have been reviewed in relation to carcinogenesis. Perturbations of the normal uptake and metabolism of carcinogens can arise through changes in microsomal enzyme activities, membrane permeabilities, and cell turnover. Metal effects on heme-dependent oxidative functions are well documented and are primarily manifested by increased heme degradation rates (microsomal heme oxygenase activity), decreased heme production (mitochondrial and cytosolic heme biosynthetic enzymes) and, in the case of a few metals, through nuclear effects of metals on the induction of microsomal enzymes. Many metals are accumulated by lysosomes, but known effects of metals on the function of these organelles in sequestering and storing organic compounds are few. Studies of changes in plasma or mitochondrial membrane permeabilities by metals have centered mainly on the susceptibility of membrane ATPase activities to metal ion alteration and on the involvement of metals in lipid peroxidation and free radical formation. Knowledge of the effects of metals on subcellular organelle functions should aid in the understanding of the mechanisms by which metal ions may play a role in the carcinogenic response.
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PMID:Relationship between metal toxicity to subcellular systems and the carcinogenic response. 702 32

Female rats were subjected to a 70% partial hepatectomy and administered either diethylnitrosamine (10 mg/kg) or the solvent, trioctanoin. After a 2 day recovery from the surgery, the rats were placed on basal diet alone or containing phenobarbital (500 mg/kg diet), mestranol (0.2 mg/kg diet), tamoxifen (250 or 500 mg/kg diet) or toremifene (250, 500 or 750 mg/kg diet) for 6 or 18 months prior to killing. The liver and kidneys were prepared for pathological diagnoses. In addition, sections of liver from the 6 month killing were frozen and serially sectioned. The sections were stained for expression of the placental isozyme of glutathione S-transferase (GST), gamma glutamyl transpeptidase (GGT), canalicular ATPase (ATP) and glucose 6-phosphatase (G6P) and scored by quantitative stereology for number and volume fraction of liver occupied by altered hepatic foci (AHF) with alterations in these markers individually and combined (ANY). Each of the agents increased the volume fraction of liver occupied by AHF when the ANY category was used. Statistical increases in both the GGT-positive and G6P-deficient AHF populations were observed in the spontaneously as well as DEN-initiated groups treated with tamoxifen or toremifene. After 18 months of administration, the highest concentration of tamoxifen increased the incidence of malignant hepatic neoplasms in non-DEN-initiated rats. Toremifene, at the highest tested dose, increased the incidence of hepatocellular carcinomas in the DEN-initiated groups to a level one-third that observed with tamoxifen administration to DEN-initiated rats. Both tamoxifen and toremifene increased the incidence of hypernephromas in previously DEN-initiated rats. While both tamoxifen and toremifene are effective promoting agents for DEN-initiated lesions, tamoxifen is more potent than toremifene in the induction of rat hepatocarcinogenesis.
Carcinogenesis 1995 Nov
PMID:Comparison of the effects of tamoxifen and toremifene on liver and kidney tumor promotion in female rats. 758 93

Diisocyanates are increasingly used for manufacturing polyurethane foam, elastomers, adhesives, coatings, insecticides and many other products. The large number of workers being exposed to these chemicals has a concentration-dependent risk of developing chronic airway disorders. The clinical role of genotoxic effects of diisocyanates demonstrable in vivo and in vitro is still unclear just as their possible cancerogenic potential. The possible initiating effect of diisocyanates in liver carcinogenesis was studied using a rat liver foci bioassay (RFLA). The RLFA is based on the histochemical demonstration of foci of hepatocytes with altered enzyme equipment, which are induced by carcinogens. These foci are generally regarded as early preneoplastic lesions. Rats were exposed either to 20 ppb TDI (Toluene diisocyanate) or 20 ppb HDI (Hexamethylene diisocyanate) for two hours a day over a period of four weeks. After a break of one week the rats received 10 mg Clophen A50/kg body weight as promotor for possible isocyanate induced tumorigenic lesions twice a week for eight weeks. For positive control the hepatocarcinogen diethylnitrosamin (DEN) was given as a single dose of 10 mg and 20 mg. All animals were sacrificed aged 16 weeks. Serial cryostat sections were prepared for ATPase and gamma GT staining. The foci number was determined and calculated as foci/animal as a mean value taken from both staining protocols. Preneoplastic liver foci were observed in positive control rats treated with a single dose of 10 mg as well as with 20 mg DEN (4.3 +/- 3.2 and 1.8 +/- 1.4 respectively). In none of the animals exposed to TDI or HDI preneoplastic foci were detectable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Induction of rat liver foci by inhaled diisocyanate exposure]. 764 58


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